U.S. patent number 7,417,054 [Application Number 11/424,751] was granted by the patent office on 2008-08-26 for naphthyridine compounds.
This patent grant is currently assigned to Janssen Pharmaceutica N.V.. Invention is credited to Nicholas I. Carruthers, John M. Keith, Michael A. Letavic, Chandravadan R. Shah.
United States Patent |
7,417,054 |
Carruthers , et al. |
August 26, 2008 |
Naphthyridine compounds
Abstract
Certain naphthyridine compounds are histamine H.sub.3 receptor
and serotonin transporter modulators useful in the treatment of
histamine H.sub.3 receptor- and serotonin-mediated diseases.
Inventors: |
Carruthers; Nicholas I. (Poway,
CA), Keith; John M. (San Diego, CA), Letavic; Michael
A. (San Diego, CA), Shah; Chandravadan R. (San Diego,
CA) |
Assignee: |
Janssen Pharmaceutica N.V.
(BG)
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Family
ID: |
37263777 |
Appl.
No.: |
11/424,751 |
Filed: |
June 16, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060287292 A1 |
Dec 21, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60692003 |
Jun 17, 2005 |
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Current U.S.
Class: |
514/300;
546/122 |
Current CPC
Class: |
A61P
25/16 (20180101); A61P 25/24 (20180101); A61P
25/08 (20180101); A61P 25/06 (20180101); A61P
3/04 (20180101); A61P 43/00 (20180101); A61P
25/20 (20180101); A61P 25/00 (20180101); A61P
25/18 (20180101); A61P 25/28 (20180101); C07D
471/04 (20130101); A61P 1/08 (20180101) |
Current International
Class: |
A01N
43/42 (20060101); A61K 31/44 (20060101); C07D
471/02 (20060101) |
Field of
Search: |
;546/122 ;514/300 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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GB |
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9640142 |
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Dec 1996 |
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WO |
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WO 01/32624 |
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May 2001 |
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WO |
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WO 2005/111036 |
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Nov 2005 |
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WO |
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|
Primary Examiner: Seaman; D. Margaret
Assistant Examiner: Rahmani; Niloofar
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. .sctn. 119(e)
of provisional application Ser. No. 60/692,003, filed on Jun. 17,
2005, which is incorporated herein by reference in its entirety.
Claims
What is claimed is:
1. A compound of formula (I): ##STR00082## wherein one or two of X,
Y, and Z is N, and the remaining of X, Y, and Z are CR.sup.5; L is
--O-- or --CH.sub.2-- and n is 1 or 2; or L is --C.ident.C-- and n
is 0 or 1; m is 0, 1, or 2; R.sup.1 is --H; or is --C.sub.1-6alkyl,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --COOC.sub.1-6alkyl, or
--COObenzyl, each optionally mono-, di-, or tri-substituted with
R.sup.a; R.sup.a is selected from the group consisting of --OH,
--OC.sub.1-6alkyl, phenyl optionally substituted with
--OC.sub.1-4alkyl or halo, --CN, --NO.sub.2, --N(R.sup.b)R.sup.c
(wherein R.sup.b and R.sup.c are independently --H or
--C.sub.1-6alkyl), --C(O)N(R.sup.b)R.sup.c,
--N(R.sup.b)C(O)R.sup.b, --N(R.sup.b)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.b)R.sup.c, --SCF.sub.3, halo, --CF.sub.3,
--OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.2 and R.sup.3
are independently selected from --H, or from the group consisting
of: A) --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl;
B) phenyl or pyridyl, optionally fused at two adjacent carbon ring
members to a three- or four-membered hydrocarbon moiety to form a
fused five- or six-membered aromatic ring, which moiety has one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), and which moiety has up to one additional
carbon atom optionally replaced by --N.dbd.; C) a 4-8 membered
heterocyclic ring, said heterocyclic ring having a carbon atom
which is the point of attachment, having 1 or 2 heteroatom members
selected from >O, >S(O).sub.0-2, and >NH, and having 0 or
1 double bonds; and D) a monocyclic aromatic hydrocarbon group
having five or six ring atoms, having a carbon atom which is the
point of attachment, having one carbon atom replaced by >O,
>S, >NH, or >N(C.sub.1-4alkyl), having up to one
additional carbon atom optionally replaced by --N.dbd., and
optionally benzofused or pyridofused; where each of A)-D) is
optionally mono-, di-, or tri-substituted with a moiety selected
from the group consisting of --OH, --C.sub.1-4alkylOH,
--OC.sub.1-6alkyl, --CN, --NO.sub.2, --N(R.sup.d)R.sup.e (wherein
R.sup.d and R.sup.e are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.d)R.sup.e, --N(R.sup.d)C(O)R.sup.d,
--N(R.sup.d)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.d)R.sup.e,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH,
--COOC.sub.1-6alkyl, --OC(O)N(R.sup.d)R.sup.e, and --OC(O)OR.sup.d;
or, alternatively, R.sup.2 and R.sup.3 may be taken together with
the nitrogen to which they are attached to form a 4-8 membered
heterocyclic ring, said heterocyclic ring having 0 or 1 additional
heteroatom members separated from the nitrogen of attachment by at
least one carbon member and selected from >O, >S(O).sub.0-2,
>NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1,
or 2 carbon members separated from the nitrogen of attachment by at
least one carbon member which is a carbonyl, optionally benzo or
pyrido fused, optionally having one carbon member that forms a
bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f
is selected from the group consisting of --C.sub.1-6alkyl
optionally mono-, di-, or tri-substituted with halo,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH,
--C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are
independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where
R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5-
or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and
--COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting
of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo,
--OH, --C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO-,
--CN, --NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h
are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g,
--N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is
--C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or
6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.y)R.sup.z, --SCF.sub.3, --OCF.sub.3, --COOH, and
--COOC.sub.1-6alkyl; R.sup.4 is --OH, --OC.sub.1-6alkyl,
--CF.sub.3, --C.sub.1-6alkyl, or halo; two R.sup.4 substituents may
be taken together to form methylene or ethylene; or one of R.sup.4
is taken together with R.sup.2 to form methylene, ethylene, or
propylene; wherein each methylene, ethylene, or propylene is
optionally substituted with --OH, --OC.sub.1-6alkyl,
--SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or halo;
R.sup.5 is selected from the group consisting of --H,
--C.sub.1-6alkyl, --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and
halo; Ar.sup.1 is an aryl or heteroaryl ring selected from the
group consisting of: a) phenyl, optionally mono-, di-, or
tri-substituted with R.sup.j or di-substituted on adjacent carbons
with --OC.sub.1-4alkyleneO- optionally mono- or di-substituted with
fluoro, --(CH.sub.2).sub.2-3NH--,
--(CH.sub.2).sub.1-2NH(CH.sub.2)--,
--(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or
--(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is
selected from the group consisting of 1) --OH, --C.sub.1-6alkyl,
--OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl,
--OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl,
--CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l
are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l,
--N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein
R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or
R.sup.m and R.sup.n taken together with their nitrogen of
attachment form a 4-8 membered heterocyclic ring having 1 or 2
heteroatom members selected from >O, >S(O).sub.0-2, >NH,
and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1
carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo,
--CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and
--COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or
partially saturated heterocyclic ring, having 1 or 2 heteroatom
members selected from >O, >S(O).sub.0-2, >NH, and
>NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring
optionally mono-, di-, or tri-substituted with R.sup.p; R.sup.p is
a substituent independently selected from the group consisting of
--OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN,
--NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are
independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl),
--C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r,
--N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent
carbon ring members to a three membered hydrocarbon moiety to form
a fused five membered aromatic ring, which moiety has one carbon
atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl),
and which moiety has up to one additional carbon atom optionally
replaced by --N.dbd., the fused rings optionally mono-, di-, or
tri-substituted with R.sup.t; R.sup.t is a substituent
independently selected from the group consisting of --OH,
--C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2,
--N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently
--H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v,
--N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.3, halo, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; c)
phenyl fused at two adjacent ring members to a four membered
hydrocarbon moiety to form a fused six membered aromatic ring,
which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the
fused rings optionally mono-, di-, or tri-substituted with R.sup.t;
d) a monocyclic aromatic hydrocarbon group having five ring atoms,
having a carbon atom which is the point of attachment, having one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., optionally mono- or di-substituted
with R.sup.t, and optionally benzofused or pyridofused at two
adjacent carbon atoms, where the benzofused or pyridofused moiety
is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a
monocyclic aromatic hydrocarbon group having six ring atoms, having
a carbon atom which is the point of attachment, having one or two
carbon atoms replaced by --N.dbd., optionally mono- or
di-substituted with R.sup.t, and optionally benzofused or
pyridofused at two adjacent carbon atoms, where the benzofused or
pyridofused moiety is optionally mono- or di-substituted with
R.sup.t; and enantiomers, diastereomers, hydrates, solvates
thereof, and pharmaceutically acceptable salts, esters and amides
thereof.
2. The compound of claim 1 wherein X is N.
3. The compound of claim 1 wherein Y is N.
4. The compound of claim 1 wherein Z is N.
5. The compound of claim 1 wherein Y and Z are N.
6. The compound of claim 1 wherein L is --O-- and n is 1.
7. The compound of claim 1 wherein L is --CH.sub.2-- and n is
1.
8. The compound of claim 1 wherein L is --C.ident.C-- and n is
0.
9. The compound of claim 1 wherein m is 0 or 1.
10. The compound of claim 1 wherein R.sup.1 is selected from the
group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,
butyl, pentyl, hexyl, benzyl, allyl, propargyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
--COOCH.sub.3, --COO-t-butyl, and --COObenzyl.
11. The compound of claim 1 wherein R.sup.1 is methyl, ethyl,
propyl, allyl, propargyl, or benzyl.
12. The compound of claim 1 wherein R.sup.1 is hydrogen or
methyl.
13. The compound of claim 1 wherein R.sup.2 and R.sup.3 are
independently selected from --H, or, optionally substituted, from
the group consisting of: A) methyl, ethyl, isopropyl, butyl,
pentyl, hexyl, allyl, propargyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, benzyl, B) phenyl,
pyridyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or
7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or
7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or
7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,
imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5,
6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,
1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,
5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, C) azetidinyl,
pyrrolidinyl, piperidinyl, and D) furanyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or
3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl,
and 3-indazolyl.
14. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally
substituted, are independently selected from methyl, ethyl,
isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and
methoxyethyl.
15. The compound of claim 1 wherein R.sup.2 and R.sup.3 are,
independently, ethyl, isopropyl, methoxyethyl, or
2-benzothiazolyl.
16. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally
substituted, are taken together with the nitrogen to which they are
attached to form a ring selected from the group consisting of
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperidinyl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.
17. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form a 4-8
membered heterocyclic ring, said heterocyclic ring selected from
piperidine, pyrrolidine, and morpholine, said ring substituted with
1 or 2 substituents R.sup.ff.
18. The compound of claim 1 wherein R.sup.ff is selected from the
group consisting of methyl, ethyl, isopropyl, butyl, hexyl,
--CF.sub.3, --CHF.sub.2, vinyl, allyl, propargyl, cyclopropyl,
cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro,
fluoro, iodo, --OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy,
isopropoxy, pentyloxy, --O(CH.sub.2).sub.2O--,
--O(CH.sub.2).sub.3O--, --CN, amino, methylamino, dimethylamino,
diethylamino, diethylcarbamoyl, methanesulfanyl, methanesulfonyl,
methanesulfonamido, --C(O)R.sup.i, --COOH, and ethoxycarbonyl.
19. The compound of claim 1 wherein R.sup.ff is selected from the
group consisting of methyl, fluoro, --OH, --CF.sub.3,
hydroxymethyl, hydroxyethyl, dimethylamino, ethoxycarbonyl, and
--O(CH.sub.2).sub.2O--.
20. The compound of claim 1 wherein R.sup.i is selected from the
group consisting of methyl, pyridyl, isopropyl, cyclobutyl,
cyclopropyl, N-methylpyrrolyl, and 1-methyl imidazolyl.
21. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form
azetidinyl, 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl,
3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl,
2-trifluoromethylpyrrolidinyl, 2- hydroxymethylpyrrolidinyl,
piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,
4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,
4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl,
3-hydroxypiperidinyl, 4-hydroxypiperidinyl,
2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl,
4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl,
3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl,
2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl,
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl, or
2-methylmorpholin-4-yl.
22. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form
piperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl,
morpholinyl, or 3-methylmorpholin-4-yl.
23. The compound of claim 1 wherein R.sup.4 is methoxy, ethoxy,
isopropoxy, pentyloxy, --CF.sub.3, methyl, ethyl, propyl, isobutyl,
pentyl, chloro, or fluoro.
24. The compound of claim 1 wherein R.sup.4 is hydroxy, methyl,
methoxy, fluoro, or --CF.sub.3.
25. The compound of claim 1 wherein two R.sup.4 are taken together
to form methylene.
26. The compound of claim 1 wherein R.sup.2 and one of R.sup.4 are
taken together to form ethylene or propylene.
27. The compound of claim 1 wherein R.sup.5 is hydrogen, methyl,
ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy,
methylsulfanyl, bromo, chloro, fluoro, or iodo.
28. The compound of claim 1 wherein R.sup.5 is hydrogen.
29. The compound of claim 1 wherein Ar.sup.1, optionally
substituted, is selected from the group consisting of: a) phenyl,
5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl,
4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl,
1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,
1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl, b) 4-, 5-, 6- or
7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or
7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or
7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or
7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,
pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4,
5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,
1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5,
6 or 7-yl, c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7-
or 8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or
8-quinazolinyl, d) furanyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or
3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl,
3-indazolyl, and e) pyridinyl, pyridinyl-N-oxide, pyrazinyl,
pyrimidinyl, pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or
4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5],
[1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6],
[2,7], [2,8]naphthyridin-1-, 3-, or 4-yl.
30. The compound of claim 1 wherein Ar.sup.1, optionally
substituted, is selected from the group consisting of phenyl,
pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thiophenyl.
31. The compound of claim 1 wherein Ar.sup.1 is selected from the
group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,
3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl,
4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl,
4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl,
2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl,
3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl,
benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,
4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl,
4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl,
4-methanesulfanylphenyl, 4-methanesulfinylphenyl,
4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,
thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl,
2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl,
2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl,
2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl,
4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl,
1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.
32. The compound of claim 1 wherein Ar.sup.1, optionally
substituted with halo, is 4-methoxyphenyl or
4-methanesulfanylphenyl.
33. A compound selected from the group consisting of:
4-(2-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(2-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine;
2-Methyl-4-phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-n-
aphthyridine;
4-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridi-
ne;
Diethyl-[3-(8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy)-pro-
pyl]-amine;
4-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6-
]-naphthyridine;
Diethyl-[3-(6-methyl-8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-ylox-
y)-propyl]-amine;
4-(4-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrah-
ydro-[2,6]-naphthyridine;
4-(4-Methoxy-phenyl)-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2,3,4-tetr-
ahydro-[2,6]-naphthyridine;
4-(4-Methoxy-phenyl)-2-methyl-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2-
,3,4-tetrahydro-[2,6]-naphthyridine;
4-(4-Methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[2,6-
]-naphthyridine;
4-(4-Methoxy-phenyl)-2-methyl-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrah-
ydro-[2,6]-naphthyridine;
4-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6-
]-naphthyridine;
4-(3-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrah-
ydro-[2,6]-naphthyridine;
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[-
2,6]-naphthyridine; 4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperid
in-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-naphthyridine;
4-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(4-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine;
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-1,2,3,4--
tetrahydro-[2,6]-naphthyridine;
Diethyl-{3-[8-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-y-
loxy]-propyl}-amine;
{3-[8-(3,4-Dichloro-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy]-
-propyl}-diethyl-amine;
7-(1-Benzyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydro-[2-
,6]-naphthyridine;
4-(4-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(3,4-Dichloro-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[-
2,6]-naphthyridine;
4-(3-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine;
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-2-methyl-
-1,2,3,4-tetrahydro-[2,6]naphthyridine;
Diethyl-{3-[8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthy-
ridin-3-yloxy]-propyl}-amine;
{3-[8-(3,4-Dichloro-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-
-3-yloxy]-propyl}-diethyl-amine;
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrah-
ydro-[2,6]-naphthyridine;
4-(3-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine;
4-(3-Chloro-4-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]naphthyridine;
4-(3-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine;
4-(3-Chloro-4-fluoro-phenyl)-2-methyl-7-(3-piperid
in-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridine;
4-(4-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]naphthyridine;
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-1,2,3,4-tet-
rahydro-[2,6]naphthyridine;
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tet-
rahydro-[2,6]-naphthyridine (enantiomer A);
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tet-
rahydro-[2,6]-naphthyridine (enantiomer B);
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-2-methyl-1,2,3-
,4-tetrahydro-[2,6]-naphthyridine;
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-2-methyl-1,-
2,3,4-tetrahydro-[2,6]naphthyridine;
4-(4-Methoxy-phenyl)-7-(piperidin-4-yloxy)-1,2,3,4-tetrahydro-[2,6]naphth-
yridine;
4-(4-Methoxy-phenyl)-2-methyl-7-(1-methyl-piperidin-4-yloxy)-1,2,-
3,4-tetrahydro-[2,6]naphthyridine;
7-(3-Piperidin-1-yl-propoxy)-4-(4-trifluoromethoxy-phenyl)-1,2,3,4-tetrah-
ydro-[2,6]naphthyridine;
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[-
2,6]-naphthyridine (enantiomer A);
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[-
2,6]-naphthyridine (enantiomer B);
7-(3-Morpholin-4-yl-propoxy)-4-phenyl-1,2,3,4-tetrahydro-[2,6]naphthyridi-
ne;
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8--
tetrahydro-[1,6]naphthyridine;
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-butyl)-5,6,7,8-tetrahyd-
ro-[1,6]-naphthyridine;
5-(4-Methoxy-phenyl)-7-methyl-2-(3-piperidin-1-yl-propoxy)-5,6,7,8-tetrah-
ydro-[1,7]naphthyridine; and
5-(4-Methoxy-phenyl)-7-methyl-2-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tet-
rahydro-[1,7]naphthyridine.
34. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an effective amount of at least one compound
of formula (I).
Description
FIELD OF THE INVENTION
The present invention provides compounds that are modulators of the
histamine H.sub.3 receptor and the serotonin transporter. More
particularly, the present invention provides naphtyridine compounds
and methods for using them to treat disorders and conditions
mediated by the histamine H.sub.3 receptor and the serotonin
transporter. As a consequence of these activities the compounds of
the present invention will have therapeutic utility for the
treatment of depression and a range of related disorders.
BACKGROUND OF THE INVENTION
Depression is a chronic illness with an estimated lifetime
prevalence of 17%. The total annual cost of depression in the USA
is estimated at $44 billion. As such, it represents a major health
problem with a serious pharmacoeconomic impact (Griffiths, R. I. et
al. Pharmacoeconomics 1999, 15(5), 495-505). Although the
biochemical basis of depression is not completely elucidated, the
most commonly accepted hypothesis states that depression occurs
when monoaminergic neurotransmission in the brain is impaired. This
theory is largely based on the observation that compounds that
improve noradrenergic and/or serotoninergic neurotransmission often
have beneficial effects in depression. Such an improvement in
monoaminergic neurotransmission can be achieved in several ways.
The biological effect of noradrenaline is terminated by two
mechanisms: reuptake from the synaptic cleft into the neuron via
the norepinephrine transporter (NET), and degradation by monoamine
oxidase (MAO). For serotonin, reuptake in the neuron via the
serotonin transporter (SERT) likewise limits its availability in
the synaptic cleft.
Currently, clinical treatment of depression relies mainly on four
types of drugs: 1) MAO inhibitors; 2) tricyclic antidepressants
(TCA); 3) selective serotonin reuptake inhibitors (SSRI); and 4)
other drugs such as reboxetine and venlafaxine. MAOs have long been
used as second-line drugs because of their potentially dangerous
side effects, and more recently, reversible MAO-A selective
inhibitors with improved profiles have been described (Bonnet, U.
CNS Drug Rev. 2002, 8(3), 283-308). TCAs such as amitryptiline
display complex pharmacological activities. They inhibit reuptake
of noradrenaline and serotonin via their respective transporters,
but also have affinity at muscarinic and histamine H.sub.1
receptors. Thus, their efficacy in treating depression is
counterbalanced by numerous unwanted side effects. The SSRIs, which
represent the largest and most successful group of antidepressants,
show a higher selectivity for the SERT than for the NET, although
the exact affinity ratio varies from drug to drug. This class of
drugs is characterized by a milder side-effect profile than the
MAO-inhibitors or the TCAs. Other drugs have been described, such
as reboxetine, which preferentially targets the NET, and
venlafaxine, which has dual activity at the SERT and NET (Olver, J.
S. et al. CNS Drugs 2001, 15(12), 941-954).
Although remarkable progress has been made in the treatment of
depression, there remains opportunity for improvement. The delay
between start of treatment and subjective improvement is a case in
point. Most drugs do not cause an improvement in the Hamilton
Rating Scale for Depression until after several weeks of treatment,
potentially leaving the patient subject to severe mental anguish
during this time. Currently available drugs have a limited response
rate and in most clinical trials only about 30% of patients show
clinical improvement (Menza, M. A. et al. J. Clin. Psych. 2000,
61(5), 378-381). Psychiatrists frequently have to evaluate several
drugs for individual patients before a satisfactory therapeutic
response is observed. Consequently there is a significant
therapeutic need for drugs with a faster onset of action, improved
side effect profiles and higher response ratio.
In order to appreciate the rationale for a combined SERT/H.sub.3
antagonist, it is necessary to understand the physiology of the
histamine H.sub.3 receptor. This receptor was described in 1983
(Arrang, J.-M. et al. Nature (London) 1983, 302(5911), 832-837) as
a presynaptic, auto-inhibitory receptor on histaminergic neurons
with a characteristic pharmacology. Activation of the H.sub.3
receptor was shown to decrease the amount of histamine released
from the nerve terminals and to inhibit the activity of histidine
decarboxylase, the rate-limiting enzyme in the synthesis of
histamine. The cloning and characterization of the human H.sub.3
receptor made it possible to explore its pharmacology (Lovenberg,
T. W. et al. Molec. Pharmacol. 1999, 55(6), 1101-1107). It is now
known that the H.sub.3 receptor is expressed on a variety of
neurons and thus, when activated, decreases the release of a number
of other neurotransmitters including noradrenaline, dopamine, and
acetylcholine (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3),
253-278). For the purpose of this discussion, we will focus on its
known effects on the release of the neurotransmitters involved in
depression, noradrenaline and serotonin. Although the
serotoninergic cell bodies are found in the dorsal raphe nucleus
while the histaminergic cells are located in the tuberomammillary
nucleus of the hypothalamus, both systems have extensive
projections throughout the brain. In several regions, such as the
suprachiasmatic nucleus (Laitinen, K. S. M. et al. Eur. J.
Pharmacol. 1995, 285(2), 159-164) and striatum both
neurotransmitters are present. It is known that activation of the
H.sub.3 receptor leads to a decreased release of serotonin, for
instance in rat cortex slices (Fink, K. et al.
Naunyn-Schmiedeberg's Arch. Pharmacol. 1990, 342(5), 513-519;
Schlicker, E. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988,
337(5), 588-590). Functional antagonists of the H.sub.3 receptor
lead to an increased release of noradrenaline in the central (mouse
cortex slices, Leurs, R. et al. J. Pharmacol. Exp. Ther. 1996,
276(3), 1009-1015; the rat hippocampus, Alvez-Rodrigues, A. et al.
Brain Res. 1998, 788(1-2), 179-186) and peripheral nervous system
(human myocardial nerves, Hatta, E. et al. J. Pharmacol. Exp. Ther.
1997, 283(2), 494-500; guinea-pig intestinal sympathetic nerves,
Blandizzi, C. et al. Br. J. Pharmacol. 2000, 129(7), 1387-1396).
However, there is little evidence that H.sub.3 receptor antagonists
alone are capable of increasing serotonin levels in vivo to those
required for antidepressant effects. Microdialysis studies of the
effect of H.sub.3 antagonists on serotonin levels in the brain of
live animals are lacking. There are sparse reports indicating that
thioperamide, an H.sub.3 receptor antagonist, may have an
antidepressant effect per se in the mouse or rat forced swim test
(Lamberti, C. et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336;
Perez-Garcia, C. et al. Psychopharmacology 1999, 142(2),
215-220).
The rationale for combining H.sub.3 receptor blockade and SERT
activity in one single molecule is the expectation that both
mechanisms will contribute synergistically to enhanced
concentrations of serotonin in the synaptic cleft. Antagonism at
the H.sub.3 receptor will provide increased release of
serotonin-containing vesicles into the synaptic cleft, and
concomitant blockade of the SERT will decrease the neuronal
reuptake of these neurotransmitter molecules. Thus, higher
concentrations of serotonin will be achieved, leading to an
enhanced therapeutic effect.
Among the prominent vegetative symptoms of depression are disturbed
sleep and the daytime fatigue associated with it. Polysomnographic
investigations have shown severe disturbances in the sleep
architecture of depressed patients. Among the typical abnormalities
observed are: discontinuous sleep, decreased slow-wave sleep,
shorter latency to REM sleep and an increased intensity and
duration of REM sleep (Riemann, D. et al. Neuropsychobiology 2002,
45(Suppl. 1), 7-12). It is believed that suppression of REM sleep
is involved in antidepressant efficacy. This is illustrated by the
dramatic success of overnight deprivation of (REM) sleep (Riemann
et al. 2002). Another non-pharmacological treatment for depression,
electroconvulsant therapy, likewise decreases REM sleep. Virtually
all of the available antidepressant drugs, regardless of their
neurochemical mechanism of action, suppress REM sleep, nefazodone
(a 5-HT.sub.2A antagonist) being the exception (Sharpley, A. L.,
Cowen, P. J. Biol. Psych. 1995, 37(2), 85-98). Antidepressant drugs
also affect slow-wave-sleep, although in a less clear manner.
H.sub.3 antagonists share this REM-sleep suppressing property and
one of the main biological effects of histamine H.sub.3 antagonists
is to improve wakefulness. Administration of H.sub.3 antagonists
has been shown to decrease REM and non-REM sleep in several animal
species. For example, the H.sub.3 antagonist carboperamide induces
waking in rats (Monti, J. M. et al. Neuropsychopharmacology 1996,
15(1), 31-35). Another H.sub.3 antagonist, thioperamide, decreased
both REM and non-REM sleep in rats (Monti, J. M. et al. Eur. J.
Pharmacol. 1991, 205(3), 283-287) and cats (Lin, J.-S. et al. Brain
Res. 1990, 523(2), 325-330). It is of interest to note that
although H.sub.3 antagonists promote wakefulness, they do so much
less potently than amphetamine derivatives. They may thus be
considered mild stimulants. The daytime correlate of disturbed
sleep is fatigue. Indeed, fatigue and lethargy are prominent
symptoms of depression, and there is considerable interest in the
use of stimulants to augment antidepressant therapy (Menza et al.,
2000). However, most of the available stimulants, like the
amphetamine derivatives and methylphenidate, carry a considerable
risk of abuse and are not ideal therapeutic choices. Modafinil, a
wake-promoting compound of unknown mechanism with a lower addictive
potential, is marketed for the treatment of narcolepsy. In a small
series of patients it was shown that addition of a low dose of
modafinil to traditional antidepressant therapy resulted in a
faster onset of action. Fatigue was particularly responsive to this
therapy, but the cognitive and physical subscales of the Hamilton
Rating Scale for Depression also improved (Menza et al., 2000). The
behavioral profile of H.sub.3 antagonists (suppression of sleep
with no stimulation of locomotor activity and limited addictive
potential) is much like that of modafinil. Therefore, a combined
H.sub.3/SSRI compound would provide symptomatic relief for the
fatigue during the first weeks of treatment, before the
mood-elevating effect of the SSRI can be noticed.
Depression is also associated with a number of cognitive symptoms
such as impaired memory and concentration difficulties. H.sub.3
antagonists have been shown to improve memory in a variety of
memory tests, including the elevated plus maze in mice (Miyazaki,
S. et al. Life Sci. 1995, 57(23), 2137-2144), a two-trial place
recognition task (Orsetti, M. et al. Behav. Brain Res. 2001,
124(2), 235-242), the passive avoidance test in mice (Miyazaki, S.
et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and
the radial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000,
21(10), 905-910). Also, in the spontaneously hypertensive rat, an
animal model for the learning impairments in attention-deficit
disorders, H.sub.3 antagonists were shown to improve memory (Fox,
G. B. et al. Behav. Brain Res. 2002, 131(1-2), 151-161). Although
no human studies are available, the evidence indicates that a
combined SERT/H.sub.3 antagonist will provide additional benefit in
combating the cognitive impairments associated with depression.
In summary, the combination of H.sub.3 receptor antagonism with
SERT activity will result in the production of drugs with an
improved antidepressant profile compared to an SSRI alone. These
drugs will be especially efficacious in ameliorating the symptoms
of fatigue, disturbed sleep and memory loss associated with
depression.
The features and advantages of the invention are apparent to one of
ordinary skill in the art. Based on this disclosure, including the
summary, detailed description, background, examples, and claims,
one of ordinary skill in the art will be able to make modifications
and adaptations to various conditions and usages. Publications
described herein are incorporated by reference in their entirety.
In addition, U.S. Patent Appl. No. 60/637,173 is also incorporated
by reference.
SUMMARY OF THE INVENTION
The invention features a compound of formula (I):
##STR00001## wherein one or two of X, Y, and Z is N, and the
remaining of X, Y, and Z are CR.sup.5; L is --O-- or --CH.sub.2--
and n is 1 or 2; or L is --C.ident.C-- and n is 0 or 1; m is 0, 1,
or 2; R.sup.1 is --H; or is --C.sub.1-6alkyl, --C.sub.3-6alkenyl,
--C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --COOC.sub.1-6alkyl, or
--COObenzyl, each optionally mono-, di-, or tri-substituted with
R.sup.a; R.sup.a is selected from the group consisting of --OH,
--OC.sub.1-6alkyl, phenyl optionally substituted with
--OC.sub.1-4alkyl or halo, --CN, --NO.sub.2, --N(R.sup.b)R.sup.c
(wherein R.sup.b and R.sup.c are independently --H or
--C.sub.1-6alkyl), --C(O)N(R.sup.b)R.sup.c,
--N(R.sup.b)C(O)R.sup.b, --N(R.sup.b)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.b)R.sup.c, --SCF.sub.3, halo, --CF.sub.3,
--OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.2 and R.sup.3
are independently selected from --H, or from the group consisting
of: A) --C.sub.1-6alkyl, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl;
B) phenyl or pyridyl, optionally fused at two adjacent carbon ring
members to a three- or four-membered hydrocarbon moiety to form a
fused five- or six-membered aromatic ring, which moiety has one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), and which moiety has up to one additional
carbon atom optionally replaced by --N.dbd.; C) a 4-8 membered
heterocyclic ring, said heterocyclic ring having a carbon atom
which is the point of attachment, having 1 or 2 heteroatom members
selected from >O, >S(O).sub.0-2, and >NH, and having 0 or
1 double bonds; and D) a monocyclic aromatic hydrocarbon group
having five or six ring atoms, having a carbon atom which is the
point of attachment, having one carbon atom replaced by >O,
>S, >NH, or >N(C.sub.1-4alkyl), having up to one
additional carbon atom optionally replaced by --N.dbd., and
optionally benzofused or pyridofused; where each of A)-D) is
optionally mono-, di-, or tri-substituted with a moiety selected
from the group consisting of --OH, --C.sub.1-4alkylOH,
--OC.sub.1-6alkyl, --CN, --NO.sub.2, --N(R.sup.d)R.sup.e (wherein
R.sup.d and R.sup.e are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.d)R.sup.e, --N(R.sup.d)C(O)R.sup.d,
--N(R.sup.d)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.d)R.sup.e,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH,
--COOC.sub.1-6alkyl, --OC(O)N(R.sup.d)R.sup.e, and --OC(O)OR.sup.d;
or, alternatively, R.sup.2 and R.sup.3 may be taken together with
the nitrogen to which they are attached to form a 4-8 membered
heterocyclic ring, said heterocyclic ring having 0 or 1 additional
heteroatom members separated from the nitrogen of attachment by at
least one carbon member and selected from >O, >S(O).sub.0-2,
>NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1,
or 2 carbon members separated from the nitrogen of attachment by at
least one carbon member which is a carbonyl, optionally benzo or
pyrido fused, optionally having one carbon member that forms a
bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f
is selected from the group consisting of --C.sub.1-6alkyl
optionally mono-, di-, or tri-substituted with halo,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH,
--C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are
independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where
R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5-
or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and
--COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting
of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo,
--OH, --C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO--,
--CN, --NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h
are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g,
--N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is
--C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or
6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.y)R.sup.z, --SCF.sub.3, --OCF.sub.3, --COOH, and
--COOC.sub.1-6alkyl; R.sup.4 is --OH, --OC.sub.1-6alkyl,
--CF.sub.3, --C.sub.1-6alkyl, or halo; two R.sup.4 substituents may
be taken together to form methylene or ethylene; or one of R.sup.4
is taken together with R.sup.2 to form methylene, ethylene, or
propylene; wherein each methylene, ethylene, or propylene is
optionally substituted with --OH, --OC.sub.1-6alkyl,
--SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or halo;
R.sup.5 is selected from the group consisting of --H,
--C.sub.1-6alkyl, --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and
halo; Ar.sup.1 is an aryl or heteroaryl ring selected from the
group consisting of: a) phenyl, optionally mono-, di-, or
tri-substituted with R.sup.j or di-substituted on adjacent carbons
with --OC.sub.1-4alkyleneO-- optionally mono- or di-substituted
with fluoro, --(CH.sub.2).sub.2-3NH--,
--(CH.sub.2).sub.1-2NH(CH.sub.2)--,
--(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or
--(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is
selected from the group consisting of 1) --OH, --C.sub.1-6alkyl,
--OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl,
--OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl,
--CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l
are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l,
--N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein
R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or
R.sup.m and R.sup.n taken together with their nitrogen of
attachment form a 4-8 membered heterocyclic ring having 1 or 2
heteroatom members selected from >O, >S(O).sub.0-2, >NH,
and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1
carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo,
--CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and
--COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or
partially saturated heterocyclic ring, having 1 or 2 heteroatom
members selected from >O, >S(O).sub.0-2, >NH, and
>NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring
optionally mono-, di-, or tri-substituted with R.sup.p; R.sup.p is
a substituent independently selected from the group consisting of
--OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN,
--NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are
independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl),
--C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r,
--N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent
carbon ring members to a three membered hydrocarbon moiety to form
a fused five membered aromatic ring, which moiety has one carbon
atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl),
and which moiety has up to one additional carbon atom optionally
replaced by --N.dbd., the fused rings optionally mono-, di-, or
tri-substituted with R.sup.t; R.sup.t is a substituent
independently selected from the group consisting of --OH,
--C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2,
--N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently
--H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v,
--N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.3, halo, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; c)
phenyl fused at two adjacent ring members to a four membered
hydrocarbon moiety to form a fused six membered aromatic ring,
which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the
fused rings optionally mono-, di-, or tri-substituted with R.sup.t;
d) a monocyclic aromatic hydrocarbon group having five ring atoms,
having a carbon atom which is the point of attachment, having one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., optionally mono- or di-substituted
with R.sup.t, and optionally benzofused or pyridofused at two
adjacent carbon atoms, where the benzofused or pyridofused moiety
is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a
monocyclic aromatic hydrocarbon group having six ring atoms, having
a carbon atom which is the point of attachment, having one or two
carbon atoms replaced by --N.dbd., optionally mono- or
di-substituted with R.sup.t, and optionally benzofused or
pyridofused at two adjacent carbon atoms, where the benzofused or
pyridofused moiety is optionally mono- or di-substituted with
R.sup.t; and enantiomers, diastereomers, hydrates, solvates and
pharmaceutically acceptable salts, esters, and amides thereof.
Isomeric forms of the compounds of formula (I), and of their
pharmaceutically acceptable salts, esters, and amides, are
encompassed within the present invention, and reference herein to
one of such isomeric forms is meant to refer to at least one of
such isomeric forms. One of ordinary skill in the art will
recognize that compounds according to this invention may exist, for
example in a single isomeric form whereas other compounds may exist
in the form of a regioisomeric mixture.
The invention also features pharmaceutical compositions containing
such compounds and methods of using such compounds and compositions
in the treatment or prevention of disease states mediated by the
histamine H.sub.3 receptor and the serotonin transporter.
Compounds of the present invention are useful in combination with
other therapeutic agents as a combination therapy method, including
use in combination with H.sub.1 receptor antagonists, H.sub.2
receptor antagonists, H.sub.3 receptor antagonists, and
neurotransmitter modulators such as serotonin-norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors
(SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin
re-uptake inhibitors (NSSRIs), and modafinil.
Additional features and advantages of the invention will become
apparent from the detailed description and examples below, and the
appended claims.
DETAILED DESCRIPTION
Particular preferred compounds of the invention comprise a compound
of formula (I), or an enantiomer, diastereomer, hydrate, solvate
thereof, or a pharmaceutically acceptable salt, amide or ester
thereof, wherein n, m, L, X, Y, Z, R.sup.1-4, and Ar.sup.1 have any
of the meanings defined hereinabove and equivalents thereof, or at
least one of the following assignments and equivalents thereof.
Such assignments may be used where appropriate with any of the
definitions, claims or embodiments defined herein:
Preferably, X is N.
Preferably, Y is N.
Preferably, Z is N.
Preferably, Y and Z are N.
Preferably, L is --O-- and n is 1.
Preferably, L is --CH.sub.2-- and n is 1.
Preferably, L is --C.ident.C-- and n is 0.
Preferably, m is 0 or 1.
Preferably, R.sup.1 is selected from the group consisting of
hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl,
benzyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylmethyl, --COOCH.sub.3, --COO-t-butyl, and
--COObenzyl.
More preferably, R.sup.1 is methyl, ethyl, propyl, allyl,
propargyl, or benzyl.
Even more preferably, R.sup.1 is hydrogen or methyl.
Preferably, R.sup.2 and R.sup.3 are independently selected from
--H, or, optionally substituted, from the group consisting of: A)
methyl, ethyl, isopropyl, butyl, pentyl, hexyl, allyl, propargyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, benzyl, B) phenyl, pyridyl, 4-, 5-, 6- or
7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or
7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or
7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or
7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,
pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4,
5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,
1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5,
6 or 7-yl, C) azetidinyl, pyrrolidinyl, piperidinyl, and D)
furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,
2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2-
or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, and
3-indazolyl.
More preferably, R.sup.2 and R.sup.3, optionally substituted, are
independently selected from methyl, ethyl, isopropyl, pyrrolidinyl,
piperidinyl, 2-benzothiazolyl, and methoxyethyl.
Even more preferably, R.sup.2 and R.sup.3 are, independently,
ethyl, isopropyl, methoxyethyl, or 2-benzothiazolyl.
In a preferred embodiment, R.sup.2 and R.sup.3, optionally
substituted, are taken together with the nitrogen to which they are
attached to form a ring selected from the group consisting of
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperidinyl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.
In an alternative embodiment, R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form a 4-8
membered heterocyclic ring, said heterocyclic ring selected from
piperidine, pyrrolidine, and morpholine, said ring substituted with
1 or 2 substituents R.sup.ff.
Preferably, R.sup.ff is selected from the group consisting of
methyl, ethyl, isopropyl, butyl, hexyl, --CF.sub.3, --CHF.sub.2,
vinyl, allyl, propargyl, cyclopropyl, cyclopentyl,
cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo,
--OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy,
pentyloxy, --O(CH.sub.2).sub.2O--, --O(CH.sub.2).sub.3O--, --CN,
amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl,
methanesulfanyl, methanesulfonyl, methanesulfonamido,
--C(O)R.sup.i, --COOH, and ethoxycarbonyl.
More preferably, R.sup.ff is selected from the group consisting of
methyl, fluoro, --OH, --CF.sub.3, hydroxymethyl, hydroxyethyl,
dimethylamino, ethoxycarbonyl, and --O(CH.sub.2).sub.2O--.
Preferably, R.sup.i is selected from the group consisting of
methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl,
N-methylpyrrolyl, and 1-methylimidazolyl.
More preferably, R.sup.2 and R.sup.3 are taken together with the
nitrogen to which they are attached to form azetidinyl,
2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl,
3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl,
2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl,
piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,
4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,
4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl,
3-hydroxypiperidinyl, 4-hydroxypiperidinyl,
2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl,
4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl,
3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl,
2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl,
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl, or
2-methylmorpholin-4-yl.
Even more preferably, R.sup.2 and R.sup.3 are taken together with
the nitrogen to which they are attached to form piperidinyl,
4-fluoropiperidinyl, 4,4-difluoropiperidinyl, morpholinyl, or
3-methylmorpholin-4-yl.
Preferably, R.sup.4 is methoxy, ethoxy, isopropoxy, pentyloxy,
--CF.sub.3, methyl, ethyl, propyl, isobutyl, pentyl, chloro, or
fluoro.
More preferably, R.sup.4 is hydroxy, methyl, methoxy, fluoro, or
--CF.sub.3.
Preferably, two R.sup.4 are taken together to form methylene.
Preferably, R.sup.2 and one of R.sup.4 are taken together to form
ethylene or propylene.
Preferably, R.sup.5 is hydrogen, methyl, ethyl, isopropyl, hexyl,
hydroxyl, methoxy, ethoxy, isopropoxy, methylsulfanyl, bromo,
chloro, fluoro, or iodo.
More preferably, R.sup.5 is hydrogen.
Preferably, Ar.sup.1, optionally substituted, is selected from the
group consisting of:
a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,
7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,
7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl,
1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,
b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl,
4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6-
or 7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or
7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl,
pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4,
5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,
1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5,
6 or 7-yl,
c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or
8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or
8-quinazolinyl,
d) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,
2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2-
or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl,
and
e) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,
pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2-
or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or
[1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6], [2,7],
[2,8]naphthyridin-1-, 3-, or 4-yl.
More preferably, Ar.sup.1, optionally substituted, is selected from
the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl,
pyrazolyl, and thiophenyl.
Even more preferably, Ar.sup.1 is selected from the group
consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,
3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl,
4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl,
4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl,
2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl,
3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl,
benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,
4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl,
4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl,
4-methanesulfanylphenyl, 4-methanesulfinylphenyl,
4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,
thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl,
2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl,
2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl,
2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl,
4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl,
1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.
In a particular embodiment, Ar.sup.1, optionally substituted with
halo, is 4-methoxyphenyl or 4-methanesulfanylphenyl.
It is understood that some compounds referred to herein are chiral
and/or have geometric isomeric centers, for example E- and Z-
isomers. The present invention encompasses all such optical,
including stereoisomers and racemic mixtures, diastereomers, and
geometric isomers that possess the activity that characterizes the
compounds of this invention. Compounds of the invention may exist
as single enantiomers, mixtures of enantiomers, or racemic
mixtures. In certain embodiments, the absolute configuration of a
single enantiomer may be unknown. In addition, certain compounds
referred to herein can exist in solvated as well as unsolvated
forms. It is understood that this invention encompasses all such
solvated and unsolvated forms that possess the activity that
characterizes the compounds of this invention.
Compounds according to the present invention that have been
modified to be detectable by some analytic technique are also
within the scope of this invention. The compounds of the present
invention may be labeled with radioactive elements such as
.sup.125I, .sup.18F, .sup.11C, .sup.64Cu, and the like for use in
imaging or for radioactive treatment of patients. An example of
such compounds is an isotopically labeled compound, such as an
.sup.18F isotopically labeled compound that may be used as a probe
in detection and/or imaging techniques, such as positron emission
tomography (PET) and single-photon emission computed tomography
(SPECT). Preferably, compounds of the present invention labeled
with .sup.18F or .sup.11C may be used as a positron emission
tomography (PET) molecular probe for studying disorders mediated by
the histamine H.sub.3 receptor and the serotonin transporter.
Another example of such compounds is an isotopically labeled
compound, such as a deuterium and/or tritium labeled compound that
may be used in reaction kinetic studies. The compounds described
herein may be reacted with appropriate functionalized radioactive
reagents using conventional chemistry to provide radiolabeled
compounds.
The present invention includes within its scope prodrugs of the
compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with a compound of formula (I) or with a
compound that converts to a compound of formula (I) in vivo after
administration to the patient. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985. In addition to salts, the invention provides the
esters, amides, and other protected or derivatized forms of the
described compounds.
Preferred compounds, which are tetrahydronaphthyridine compounds,
are selected from the group consisting of:
TABLE-US-00001 EX CHEMICAL NAME 1
4-(2-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 2
4-(2-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 3
2-Methyl-4-phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-
[2,6]-naphthyridine; 4
4-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-
[2,6]naphthyridine; 5
Diethyl-[3-(8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy)-
propyl]-amine; 6
4-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 7
Diethyl-[3-(6-methyl-8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-
3-yloxy)-propyl]-amine; 8
4-(4-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 9
4-(4-Methoxy-phenyl)-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 10
4-(4-Methoxy-phenyl)-2-methyl-7-[2-(1-methyl-pyrrolidin-2-yl)-
ethoxy]-1,2,3,4-tetrahydro-[2,6]-naphthyridine; 11
4-(4-Methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 12
4-(4-Methoxy-phenyl)-2-methyl-7-(3-morpholin-4-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 13
4-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 14
4-(3-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 15
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 16
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 17
4-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 18
4-(4-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 19
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 20
Diethyl-{3-[8-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-
[2,6]naphthyridin-3-yloxy]-propyl}-amine; 21
{3-[8-(3,4-Dichloro-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-
yloxy]-propyl}-diethyl-amine; 22
7-(1-Benzyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 23
4-(4-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 24
4-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 25
4-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 26
4-(3,4-Dichloro-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 27
4-(3-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 28
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-2-
methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine; 29
Diethyl-{3-[8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-
[2,6]naphthyridin-3-yloxy]-propyl}-amine; 30
{3-[8-(3,4-Dichloro-phenyl)-6-methyl-5,6,7,8-tetrahydro-
[2,6]naphthyridin-3-yloxy]-propyl}-diethyl-amine; 31
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine; 32
4-(3-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 33
4-(3-Chloro-4-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 34
4-(3-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine; 35
4-(3-Chloro-4-fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-
propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridine; 36
4-(4-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 37
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-
1,2,3,4-tetrahydro-[2,6]naphthyridine; 38
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine (enantiomer A); 39
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-
1,2,3,4-tetrahydro-[2,6]-naphthyridine (enantiomer B); 40
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-2-
methyl-1,2,3,4-tetrahydro-[2,6]-naphthyridine; 41
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-2-
methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine; 42
4-(4-Methoxy-phenyl)-7-(piperidin-4-yloxy)-1,2,3,4-tetrahydro-
[2,6]naphthyridine; 43
4-(4-Methoxy-phenyl)-2-methyl-7-(1-methyl-piperidin-4-yloxy)-
1,2,3,4-tetrahydro-[2,6]naphthyridine; 44
7-(3-Piperidin-1-yl-propoxy)-4-(4-trifluoromethoxy-phenyl)-1,2,3,4-
tetrahydro-[2,6]naphthyridine; 45
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine (enantiomer A); 46
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
tetrahydro-[2,6]-naphthyridine (enantiomer B); 47
7-(3-Morpholin-4-yl-propoxy)-4-phenyl-1,2,3,4-tetrahydro-
[2,6]naphthyridine; 48
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-
5,6,7,8-tetrahydro-[1,6]naphthyridine; 49
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-butyl)-5,6,7,8-
tetrahydro-[1,6]-naphthyridine; 50
5-(4-Methoxy-phenyl)-7-methyl-2-(3-piperidin-1-yl-propoxy)-
5,6,7,8-tetrahydro-[1,7]naphthyridine; and 51
5-(4-Methoxy-phenyl)-7-methyl-2-(4-piperidin-1-yl-but-1-ynyl)-
5,6,7,8-tetrahydro-[1,7]naphthyridine.
The features and advantages of the invention are apparent to one of
ordinary skill in the art. Based on this disclosure, including the
summary, detailed description, background, examples, and claims,
one of ordinary skill in the art will be able to make modifications
and adaptations to various conditions and usages. Publications
described herein are incorporated by reference in their entirety.
Where chemical symbols are used, it is understood that they are
read from left to right, and that otherwise their spatial
orientation has no significance.
The compounds as described above may be made according to processes
within the skill of the art and/or that are described in the
schemes and examples that follow. To obtain the various compounds
herein, starting materials may be employed that carry the
ultimately desired substituents though the reaction scheme with or
without protection as appropriate. This may be achieved by means of
conventional protecting groups, such as those described in
"Protective Groups in Organic Chemistry", ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd ed., John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
Alternatively, it may be necessary to employ, in the place of the
ultimately desired substituent, a suitable group that may be
carried through the reaction scheme and replaced as appropriate
with the desired substituent. Such compounds, precursors, or
prodrugs are also within the scope of the invention. Reactions may
be performed between the melting point and the reflux temperature
of the solvent, and preferably between 0.degree. C. and the reflux
temperature of the solvent.
The naphthyridine compounds of formula (I) may be prepared by a
number of reaction schemes. Access to compounds of formula (I) is
described in Schemes A-D. Persons skilled in the art will recognize
that certain compounds are more advantageously produced by one
scheme as compared to the other.
##STR00002##
Referring to Scheme A, reagents of formulae A1, A2, and A6 are
commercially available, or are prepared according to known methods.
Derivatives A1 are reacted with alkylating agents A2, where LG is a
halide or tosylate leaving group, using a suitable base such as
NaH, at temperatures between -78.degree. C. and room temperature,
to form ethers A3. Alternatively, derivatives A1 may be reacted
with alcohols A2 (where LG is OH) according to a Williamson ether
synthesis protocol (using a suitable base such as K.sub.2CO.sub.3,
Na.sub.2CO.sub.3, or NaH, in a solvent such as acetonitrile, with
or without catalytic KI or NaI) or under Mitsunobu conditions.
Ethers A3 are reacted with a strong base such as LDA, in a solvent
such as THF, at reduced temperatures such as -78.degree. C., and
subsequently with a CO.sub.2 equivalent, such as DMF, ethyl
chloroformate, or the like, to install an aldehyde or related
functionality that may be converted to aldehydes A4. Where Z is N,
compounds A4 may be alternatively be prepared according to Kelly,
S. A. et al. Org. Biomol. Chem. 2003, 1(16), 2865-2876. Aldehydes
A4 may be protected as their acetal analogs A5 according to
standard methods, such as treatment with (MeO).sub.3CH and
H.sub.2SO.sub.4 in MeOH. Acetals A5 may be also formed in situ or
during purification of aldehydes A4. Acetals A5 are then reacted
under halogen-metal exchange conditions, such as with BuLi, in a
solvent such as THF or toluene, at reduced temperatures such as
-78.degree. C., and coupled with nitroolefins A6, to provide
nitroalkanes A7. Where X is N, compounds of A7 may alternatively be
prepared from 2-chloro-5-hydroxy-nicotinic acid (Nemec, J. et al.
J. Het. Chem. 1974, 11(4), 569-573) using methods known in the art.
Nitroalkanes are reduced, preferably by treatment with Zn in acetic
acid at elevated temperatures, effecting cyclization to form
naphthyridines A8. Formation of cyclized products may require
treatment with a strong acid such as 6 N HCl, and/or reduction of
an intermediate imine with a reducing agent such as NaBH.sub.4 and
the like. Compounds A8 may be further processed to other compounds
of formula (I) by reductive amination or acylation. Other
embodiments of R.sup.1 may be introduced by acylation or peptide
coupling protocols known to one skilled in the art.
##STR00003##
Referring to Scheme B, compounds of formula (I) may also be
prepared from methyl ethers B1, which are accessible according to
the methods described in Scheme A. Deprotection of the methyl group
may be accomplished by treatment under acidic conditions, such as 4
M HCl at elevated temperatures or TMSCl/NaI. Alternatively, where
the methoxy group is not ortho to a ring N, deprotection may be
effected by treatment with BBr.sub.3. The resulting alcohols B2 may
be alkylated or coupled with alkylating agents A2 as described in
Scheme A. Alternatively, alcohols B2 may be alkylated with alkyl
iodides B3, using a base such as NaH, in a solvent such as DMF or
THF or mixtures thereof; the resulting intermediate alkyl chlorides
(not shown) may be displaced with suitable amines R.sup.3R.sup.2NH,
in the presence of a base such as Na.sub.2CO.sub.3, in a polar
solvent such as n-butanol, with or without catalytic NaI, to form
compounds of formula (I).
##STR00004##
Referring to Scheme C, acid C1 is commercially available or may be
prepared according to the procedures described by Gero, T. W. et
al. (Synth. Commun. 1989, 19(3-4), 553-559). The acid functionality
is reduced using conditions known to one skilled in the art.
Preferred conditions involve: first converting the acid to a
carbonate, such as an isobutyl carbonate, by treatment with
isobutyl chloroformate in the presence of a tertiary amine base
such as Et.sub.3N, in a solvent such as THF; and then reducing the
intermediate with a suitable reducing agent such as NaBH.sub.4.
Alcohols C2 are then converted to amines C3 by: first converting
alcohol functionality into a suitable leaving group such as a
mesylate or halide, and preferably to the corresponding mesylates
through treatment with MsCl, in the presence of a tertiary amine
base such as Et.sub.3N or DIPEA, in a solvent such as
CH.sub.2Cl.sub.2 or THF; and then displacing the leaving group with
amines R.sup.1NH.sub.2, with or without the addition of a base such
as Et.sub.3N, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, or excess
R.sup.1NH.sub.2, in a polar solvent such as EtOH or n-butanol. One
skilled in the art will recognize that where the ultimately desired
R.sup.1 is an acyl group, a suitable nitrogen protecting group,
such as a benzyl protecting group, may be installed at this stage,
and subsequently removed and replaced with the appropriate acyl
group at the end of the sequence as described in Scheme A. Amines
C3 may then be reacted with acylating agents C4 to form amides C5.
Where LG is a halide, such as chloride, reactions include treatment
with a suitable tertiary amine base, such as Et.sub.3N or
N-methylmorpholine, in a solvent such as CH.sub.2Cl.sub.2 or THF.
Where LG is OH, coupling is effected under peptide coupling
conditions known in the art. Cyclization to form compounds C6 is
performed in the presence of a strong base, such as NaH, in a
polar, aprotic solvent such as DMSO. Reduction of compounds C6,
using a reducing agent such as BH.sub.3, in a solvent such as THF,
provides aryl bromides C7. Preferably, reductions are performed at
elevated temperatures. Bromides C7 may then be coupled with alkynes
C8, under Sonogashira or other palladium-catalyzed conditions, to
provide alkynes C9, which are embodiments of formula (I). Preferred
conditions include a palladium catalyst such as
(Ph.sub.3P).sub.2PdCl.sub.2, with or without additives such as
Et.sub.2NH, CuI, and Ph.sub.3P, or the like, in a polar solvent
such as DMF or NMP. Preferably, reactions are performed at elevated
temperatures. Alkynes C9 may then be hydrogenated, in the presence
of a suitable catalyst such as Pd on BaSO4, in a solvent such as
EtOH, to form alkanes C10, which are embodiments of formula
(I).
##STR00005##
Referring to Scheme D, alcohols D1 may be prepared according to the
methods described in Scheme A and B, and may be activated to an
aryl chloride, aryl bromide, or aryl triflate by treatment with a
reagent such as POCl.sub.3 or triflic anhydride to form chlorides
D2. Preferably, reactions are performed with POCl.sub.3 at elevated
temperatures. Activated compounds D2 may be coupled with alkynes C8
and reduced to form alkynes D3 and alkanes D4, respectively, as
described in Scheme C.
Those skilled in the art will recognize that, if required, a group
such as a protected amino group or surrogate, may be used in place
of "R" and later transformed into the group "R".
Compounds prepared according to the schemes described above may be
obtained as single enantiomers, diastereomers, or regioisomers, or
as racemic mixtures or mixtures of enantiomers, diastereomers, or
regioisomers. Where regioisomeric or diastereomeric mixtures are
obtained, isomers may be separated using conventional methods such
as chromatography or crystallization. Where racemic (1:1) and
non-racemic (not 1:1) mixtures of enantiomers are obtained, single
enantiomers may be isolated using conventional separation methods
known to one skilled in the art. Particularly useful separation
methods may include chiral chromatography, recrystallization,
resolution, diastereomeric salt formation, or derivatization into
diastereomeric adducts followed by separation.
For therapeutic use, salts of the compounds of the present
invention are those that are pharmaceutically acceptable. However,
salts of acids and bases that are non-pharmaceutically acceptable
may also find use, for example, in the preparation or purification
of a pharmaceutically acceptable compound. All salts, whether
pharmaceutically acceptable or not are included within the ambit of
the present invention.
Pharmaceutically acceptable salts, esters, and amides of compounds
according to the present invention refer to those salt, ester, and
amide forms of the compounds of the present invention which would
be apparent to the pharmaceutical chemist, i.e., those which are
non-toxic and which would favorably affect the pharmacokinetic
properties of said compounds of the present invention. Those
compounds having favorable pharmacokinetic properties would be
apparent to the pharmaceutical chemist, i.e., those which are
non-toxic and which possess such pharmacokinetic properties to
provide sufficient palatability, absorption, distribution,
metabolism and excretion. Other factors, more practical in nature,
which are also important in the selection, are cost of raw
materials, ease of crystallization, yield, stability,
hygroscopicity and flowability of the resulting bulk drug.
Examples of acids that may be used in the preparation of
pharmaceutically acceptable salts include the following: acetic
acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid,
alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,
benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric
acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, cinnamic acid, citric
acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric
acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
Compounds of the present invention containing acidic protons may be
converted into their therapeutically active non-toxic metal or
amine addition salt forms by treatment with appropriate organic and
inorganic bases. Appropriate base salt forms comprise, for example,
the ammonium salts; the alkali and earth alkaline metal salts (e.g.
lithium, sodium, potassium, magnesium, calcium salts, which may be
prepared by treatment with, for example, magnesium hydroxide,
calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium
hydroxide); and amine salts made with organic bases (e.g. primary,
secondary and tertiary aliphatic and aromatic amines such as
L-arginine, benethamine, benzathine, choline, deanol,
diethanolamine, diethylamine, dimethylamine, dipropylamine,
diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine,
hydrabamine, 1H-imidazole, L-lysine, morpholine,
4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine,
propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine,
quinuclidine, quinoline, isoquinoline, secondary amines,
triethanolamine, trimethylamine, triethylamine,
N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,
and tromethamine). See, e.g., S. M. Berge, et al., "Pharmaceutical
Salts", J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein
by reference.
Pharmaceutically acceptable esters and amides are those that are
within a reasonable benefit/risk ratio, pharmacologically effective
and suitable for contact with the tissues of patients without undue
toxicity, irritation, or allergic response. Representative
pharmaceutically acceptable amides of the invention include those
derived from ammonia, primary C.sub.1-6alkyl amines and secondary
di(C.sub.1-6alkyl) amines. Secondary amines include 5- or
6-membered heterocyclic or heteroaromatic ring moieties containing
at least one nitrogen atom and optionally between 1 and 2
additional heteroatoms. Preferred amides are derived from ammonia,
C.sub.1-3alkyl primary amines, and di(C.sub.1-2alkyl)amines.
Representative pharmaceutically acceptable esters of the invention
include C.sub.1-7alkyl, C.sub.5-7cycloalkyl, phenyl, substituted
phenyl, and phenylC.sub.1-6alkyl- esters. Preferred esters include
methyl esters. Furthermore, examples of suitable esters include
such esters where one or more carboxyl substituents is replaced
with p-methoxybenzyloxy-carbonyl, 2,4,6-trimethyl
benzyloxy-carbonyl, 9-anthryloxycarbonyl, CH.sub.3SCH.sub.2COO--,
tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxy-carbonyl,
fur-2-yloxycarbonyl, benzoylmethoxycarbonyl,
p-nitrobenzyloxy-carbonyl, 4-pyridyl methoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl,
triphenylmethoxycarbonyl, adamantyloxycarbonyl,
2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, or
tetrahydropyran-2-yloxycarbonyl.
The compounds of the present invention are modulators of the
histamine H.sub.3 receptor and of the serotonin transporter, and as
such, the compounds are useful in the treatment of histamine
H.sub.3 and serotonin-mediated disease states. Compounds of the
present invention possess serotonin transporter and H.sub.3
receptor modulating activity. As modulators, the compounds may act
as antagonists or agonists. The effect of an antagonist may also be
produced by an inverse agonist.
The compounds of the present invention are useful in methods for
treating or preventing neurologic or CNS disorders including
sleep/wake and arousal/vigilance disorders (e.g. insomnia, jet lag,
and disturbed sleep), attention deficit hyperactivity disorders
(ADHD), attention-deficit disorders, learning and memory disorders,
learning impairment, memory impairment, memory loss, cognitive
dysfunction, migraine, neurogenic inflammation, dementia, mild
cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,
narcolepsy with or without associated cataplexy, cataplexy,
disorders of sleep/wake homeostasis, idiopathic somnolence,
excessive daytime sleepiness (EDS), circadian rhythym disorders,
sleep/fatigue disorders, fatigue, drowsiness associated with sleep
apnea, sleep impairment due to perimenopausal hormonal shifts,
Parkinson's-related fatigue, MS-related fatigue, depression-related
fatigue, chemotherapy-induced fatigue, work-related fatigue, eating
disorders, obesity, motion sickness, vertigo, schizophrenia,
substance abuse, bipolar disorders, manic disorders and depression.
Said methods comprise the step of administering to a mammal
suffering therefrom an effective amount of at least one compound of
the present invention.
Particularly, as modulators of the histamine H.sub.3 receptor and
the serotonin transporter, the compounds of the present invention
may be used in the treatment or prevention of depression, disturbed
sleep, fatigue, lethargy, cognitive impairment, memory impairment,
memory loss, learning impairment, and attention-deficit
disorders.
The present invention also contemplates a method of treating or
preventing a disease or condition mediated by the histamine H.sub.3
receptor and the serotonin transporter with a combination therapy,
comprising administering at least one compound of the present
invention in combination with one or more therapeutic agents.
Suitable therapeutic agents include: H.sub.1 receptor antagonists,
H.sub.2 receptor antagonists, H.sub.3 receptor antagonists, and
neurotransmitter modulators such as serotonin-norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors
(SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin
re-uptake inhibitors (NSSRIs), and modafinil. In a particular
embodiment, a combination therapy method includes administering at
least one compound of the present invention and administering
modafinil, for example, for the treatment of narcolepsy, excessive
daytime sleepiness (EDS), Alzheimer's disease, depression,
attention-deficit disorders, MS-related fatigue, post-anesthesia
grogginess, cognitive impairment, schizophrenia, spasticity
associated with cerebral palsy, age-related memory decline,
idiopathic somnolence, or jet-lag.
Compounds of the present invention may be administered in
pharmaceutical compositions to treat patients (humans and other
mammals) with disorders mediated by the H.sub.3 receptor and
serotonin transporter. Thus, the invention features pharmaceutical
compositions containing at least one compound of the present
invention and a pharmaceutically acceptable carrier. A composition
of the invention may further include at least one other therapeutic
agent (for example, a combination formulation or combination of
differently formulated active agents for use in a combination
therapy method).
The present invention also features methods of using or preparing
or formulating such pharmaceutical compositions. The pharmaceutical
compositions can be prepared using conventional pharmaceutical
excipients and compounding techniques known to those skilled in the
art of preparing dosage forms. It is anticipated that the compounds
of the invention can be administered by oral, parenteral, rectal,
topical, or ocular routes, or by inhalation. Preparations may also
be designed to give slow release of the active ingredient. The
preparation may be in the form of tablets, capsules, sachets,
vials, powders, granules, lozenges, powders for reconstitution,
liquid preparations, or suppositories. Preferably, compounds may be
administered by intravenous infusion or topical administration, but
more preferably by oral administration.
For oral administration, the compounds of the invention can be
provided in the form of tablets or capsules, or as a solution,
emulsion, or suspension. Tablets for oral use may include the
active ingredient mixed with pharmaceutically acceptable excipients
such as inert diluents, disintegrating agents, binding agents,
lubricating agents, sweetening agents, flavoring agents, coloring
agents and preservatives agents. Suitable inert fillers include
sodium and calcium carbonate, sodium and calcium phosphate,
lactose, starch, sugar, glucose, methyl cellulose, magnesium
stearate, mannitol, sorbitol, and the like; typical liquid oral
excipients include ethanol, glycerol, water and the like. Starch,
polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline
cellulose, and alginic acid are suitable disintegrating agents.
Binding agents may include starch and gelatin. The lubricating
agent, if present, will generally be magnesium stearate, stearic
acid or talc. If desired, the tablets may be coated with a material
such as glyceryl monostearate or glyceryl distearate to delay
absorption in the gastrointestinal tract, or may be coated with an
enteric coating. Capsules for oral use include hard gelatin
capsules in which the active ingredient is mixed with a solid,
semi-solid, or liquid diluent, and soft gelatin capsules wherein
the active ingredient is mixed with water, an oil such as peanut
oil or olive oil, liquid paraffin, a mixture of mono and
di-glycerides of short chain fatty acids, polyethylene glycol 400,
or propylene glycol.
Liquids for oral administration may be suspensions, solutions,
emulsions or syrups or may be presented as a dry product for
reconstitution with water or other suitable vehicles before use.
Compositions of such liquid may contain pharmaceutically-acceptable
excipients such as suspending agents (for example, sorbitol, methyl
cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminium stearate gel and the like);
non-aqueous vehicles, which include oils (for example, almond oil
or fractionated coconut oil), propylene glycol, ethyl alcohol or
water; preservatives (for example, methyl or propyl
p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin;
and, if needed, flavoring or coloring agents.
The compounds of this invention may also be administered by
non-oral routes. The compositions may be formulated for rectal
administration as a suppository. For parenteral use, including
intravenous, intramuscular, intraperitoneal, or subcutaneous
routes, the compounds of the invention will generally be provided
in sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity or in parenterally acceptable oil.
Suitable aqueous vehicles include Ringer's solution and isotonic
sodium chloride. Such forms will be presented in unit dose form
such as ampules or disposable injection devices, in multi-dose
forms such as vials from which the appropriate dose may be
withdrawn, or in a solid form or pre-concentrate that can be used
to prepare an injectable formulation. Another mode of
administration of the compounds of the invention may utilize a
patch formulation to affect transdermal delivery. The compounds of
this invention may also be administered by inhalation, via the
nasal or oral routes using a spray formulation consisting of the
compound of the invention and a suitable carrier.
Methods are known in the art for determining effective doses for
therapeutic and prophylactic purposes for the pharmaceutical
compositions or the drug combinations of the present invention,
whether or not formulated in the same composition. The specific
dosage level required for any particular patient will depend on a
number of factors, including severity of the condition being
treated, the route of administration, and the weight of the
patient. For therapeutic purposes, "effective dose" or "effective
amount" refers to that amount of each active compound or
pharmaceutical agent, alone or in combination, that elicits the
biological or medicinal response in a tissue system, animal, or
human that is being sought by a researcher, veterinarian, medical
doctor, or other clinician, which includes alleviation of the
symptoms of the disease or disorder being treated. For prophylactic
purposes (i.e., inhibiting the onset or progression of a disorder),
the term "effective dose" or "effective amount" refers to that
amount of each active compound or pharmaceutical agent, alone or in
combination, that inhibits in a subject the onset or progression of
a disorder as being sought by a researcher, veterinarian, medical
doctor, or other clinician, the delaying of which disorder is
mediated, at least in part, by the modulation of the histamine
H.sub.3 receptor and/or the serotonin transporter. Thus, the
present invention provides combinations of two or more drugs
wherein, for example, (a) each drug is administered in an
independently therapeutically or prophylactically effective amount;
(b) at least one drug in the combination is administered in an
amount that is sub-therapeutic or sub-prophylactic if administered
alone, but is therapeutic or prophylactic when administered in
combination with the second or additional drugs according to the
invention; or (c) both drugs are administered in an amount that is
sub-therapeutic or sub-prophylactic if administered alone, but are
therapeutic or prophylactic when administered together.
Combinations of three or more drugs are analogously possible.
Methods of combination therapy include co-administration of a
single formulation containing all active agents; essentially
contemporaneous administration of more than one formulation; and
administration of two or more active agents separately
formulated.
It is anticipated that the daily dose (whether administered as a
single dose or as divided doses) will be in the range 0.01 to 1000
mg per day, more usually from 1 to 500 mg per day, and most usually
from 10 to 200 mg per day. Expressed as dosage per unit body
weight, a typical dose will be expected to be between 0.0001 mg/kg
and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most
especially between 0.15 mg/kg and 2.5 mg/kg.
Preferably, oral doses range from about 0.05 to 200 mg/kg, daily,
taken in 1 to 4 separate doses. Some compounds of the invention may
be orally dosed in the range of about 0.05 to about 50 mg/kg daily,
others may be dosed at 0.05 to about 20 mg/kg daily, while still
others may be dosed at 0.1 to about 10 mg/kg daily. Infusion doses
can range from about 1 to 1000 .mu.g/kg/min of inhibitor, admixed
with a pharmaceutical carrier over a period ranging from several
minutes to several days. For topical administration compounds of
the present invention may be mixed with a pharmaceutical carrier at
a concentration of about 0.1% to about 10% of drug to vehicle.
EXAMPLES
In order to illustrate the invention, the following examples are
included. These examples do not limit the invention. They are only
meant to suggest a method of practicing the invention. Those
skilled in the art may find other methods of practicing the
invention, which are obvious to them. However, those methods are
deemed to be within the scope of this invention.
Protocol for Preparative Reversed-Phase HPLC
TABLE-US-00002 Instrument: Gilson .RTM. Column: YMC-Pack ODS-A, 5
.mu.m, 75 .times. 30 mm Flow rate: 25 mL/min Detection: .lamda. =
220 & 254 nm Gradient (CH.sub.3CN/H.sub.2O, 0.05%
trifluoroacetic acid) 1) 0.0 min 15% CH.sub.3CN/85% H.sub.2O 2)
20.0 min 99% CH.sub.3CN/1% H.sub.2O
Protocol for HPLC (Reversed-Phase)
TABLE-US-00003 Method A: Instrument: Hewlett Packard Series 1100
Column: Agilent ZORBAX .RTM. Bonus RP, 5 .mu.m, 4.6 .times. 250 mm
Flow rate: 1 mL/min Detection: .lamda. = 220 & 254 nm Gradient
(CH.sub.3CN/H.sub.2O, 0.05% trifluoroacetic acid) 1) 0.0 min 1%
CH.sub.3CN/99% H.sub.2O 2) 20.0 min 99% CH.sub.3CN/1% H.sub.2O
TABLE-US-00004 Method B: Instrument: Hewlett Packard HPLC Column:
Agilent ZORBAX .RTM. Eclipse XDB-C8, 5 .mu.m, 4.6 .times. 150 mm
Flow rate: 1 mL/min Detection: .lamda. = 220 & 254 nm Gradient
(CH.sub.3CN/H.sub.2O, 0.05% trifluoroacetic acid) 1) 0.0 min 1%
CH.sub.3CN/99% H.sub.2O 2) 8.0 min 99% CH.sub.3CN/1% H.sub.2O 3)
12.0 min 99% CH.sub.3CN/1% H.sub.2O
Protocol for Preparative SFC
Instrument: Thar Technologies.RTM. Column: Chiracel AD, 10 .mu.m,
250.times.20 mm Flow rate: 37 gm/min Detection: .lamda.=220 &
254 nm Mobile phase: Isocratic 30% IPA/70% CO.sub.2 Pressure: 150
Bar Temperature: 35.degree. C.
Protocol for Analytical SFC
Instrument: Jasco.RTM. Column: Chiracel AD, 10 .mu.m, 250.times.4.6
mm Flow rate: 1 gm/min Detection: .lamda.=220 & 254 nm Mobile
phase: Isocratic 30% IPA/70% CO.sub.2 Pressure: 150 Bar
Temperature: 35.degree. C.
Mass spectra were obtained on an Agilent series 1100 MSD using
electrospray ionization (ESI) in either positive or negative modes
as indicated. Calculated mass corresponds to the exact mass.
Thin-layer chromatography was performed using Merck silica gel 60
F.sub.254 2.5 cm.times.7.5 cm 250 .mu.m or 5.0 cm.times.10.0 cm 250
.mu.m pre-coated silica gel plates. Preparative thin-layer
chromatography was performed using EM Science silica gel 60
F.sub.254 20 cm.times.20 cm 0.5 mm pre-coated plates with a 20
cm.times.4 cm concentrating zone.
NMR spectra were obtained on either a Bruker model DPX400 (400 MHz)
or DPX500 (500 MHz) spectrometer. The format of the .sup.1H NMR
data below is: chemical shift in ppm down field of the
tetramethylsilane reference (multiplicity, coupling constant J in
Hz, integration).
Normal phase flash column chromatography (FCC) was typically
performed with RediSep.RTM. silica gel columns.
Chiral chromatography was performed using SFC HPLC (Chiralpak AD-h
column), IPA/MeOH/CO.sub.2, or by chiral HPLC (21.times.250 mm
Chiracel AD-H, 5 .mu.M (Chiral Technologies), 0.2% diethylamine in
EtOH, 8 mL/min).
Where a potential chiral center is designated with a solid bond
(not bold or hashed), the structure is meant to refer to a racemic
mixture, a mixture of enantiomers, or a single enantiomer as
described. Where a single enantiomer is described without
enantiomeric designation at the chiral center, it is understood
that the absolute configuration of the single enantiomer is
unknown.
Unless otherwise specified, solutions were dried over
Na.sub.2SO.sub.4, and were concentrated using a rotary evaporator
under reduced pressure.
##STR00006##
Example 1
4-(2-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
##STR00007##
Step A. 5-Bromo-2-(3-piperidin-1-yl-propoxy)-pyridine. A solution
of 3-piperidin-1-yl-propan-1-ol (5.8 mL, .about.4.6 g, 32.2 mmol)
in DMF (250 mL) was treated with NaH (60% in oil; 2.58 g, 67.3
mmol). The mixture was stirred at room temperature (rt) for 1 h,
and then was treated with 2,5-dibromopyridine (6.81 g, 28.7 mmol).
After 18 h, MeOH (10 mL) was added slowly, and the mixture was
diluted with satd. aq. NaHCO.sub.3, and extracted with EtOAc
(2.times.). The organic layers were combined, washed with H.sub.2O
(3.times.), dried, and concentrated to give oil. The residue was
purified (SiO.sub.2; 2 M NH.sub.3 in MeOH/DCM) to give the title
compound (7.38 g, 86%) as an off-white solid. MS (ESI): mass calcd.
for C.sub.13H.sub.19BrN.sub.2O, 298.07; m/z found, 299.3
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.17 (dd, J=2.5, 0.6, 1H),
7.62 (dd, J=8.8, 2.5, 1H), 6.64 (dd, J=8.8, 0.6, 1H), 4.28 (t,
J=6.5, 2H), 2.47-2.33 (m, 6H), 2.00-1.90 (m, 2H), 1.62-1.56 (m,
4H), 1.47-1.40 (m, 2H).
##STR00008##
Step B.
5-Bromo-4-dimethoxymethyl-2-(3-piperidin-1-yl-propoxy)-pyridine. A
-78.degree. C. of iPr.sub.2NH (1.7 mL, 12.2 mmol) in THF (35 mL)
was treated with n-BuLi (2.5 M in hexanes; 4.8 mL). The mixture was
allowed to warm to 0.degree. C., then was cooled to -78.degree. C.
and treated with a pre-cooled, 0.degree. C. solution of
5-bromo-2-(3-piperidin-1-yl-propoxy)-pyridine (3.60 g, 12.0 mmol)
in THF (25 mL) via cannula. After 30 min, DMF (1.8 mL, 23.3 mmol)
was added, and the mixture was allowed to warm to 0.degree. C. The
mixture was diluted with satd. aq. NaHCO.sub.3 and extracted with
DCM. The organic layer was dried and concentrated to give an oil.
The oil was purified (SiO.sub.2; 2 M NH.sub.3 in MeOH/DCM) to give
a mixture of the aldehyde and a methanol hemi-acetal, which was
used directly in the next step. A 0.degree. C. solution of the
mixture in MeOH (20 mL) was treated with conc. H.sub.2SO.sub.4 (1
mL). After 2.5 days at 0.degree. C., the mixture was concentrated,
neutralized with satd. aq. NaHCO.sub.3, and extracted with DCM. The
organic layer was dried and concentrated. The crude mixture was
chromatographed (SiO.sub.2; 1-10% 2 M NH.sub.3 in MeOH/DCM) to give
the title compound (1.66 g, 37%) as an oil. MS (ESI): mass calcd.
for C.sub.16H.sub.25BrN.sub.2O.sub.3, 372.10; m/z found, 373.40
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.21 (s, 1H), 6.98 (s, 1H),
4.29 (t, J=6.5, 2H), 3.38 (s, 6H), 2.48-2.35 (m, 6H), 2.00-1.92 (m,
4H), 1.47-1.40 (m, 2H).
##STR00009##
Step C.
1-(3-{3-Dimethoxymethyl-4-[1-(2-fluoro-phenyl)-2-nitro-ethyl]-phe-
noxy}-propyl)-piperidine. A -78.degree. C. solution of
5-bromo-4-dimethoxymethyl-2-(3-piperidin-1-yl-propoxy)-pyridine
(359 mg, 0.962 mmol) in THF (8 mL) was treated with n-BuLi (2.5 M
in hexanes; 0.4 mL). After 20 min at -78.degree. C., the mixture
was treated with a solution of 1-fluoro-2-(2-nitro-vinyl)-benzene
(171 mg, 1.02 mmol) in THF (5 mL). After 20 min at -78.degree. C.,
the mixture was treated with acetic acid (1 mL) and was allowed to
warm to 0.degree. C. The mixture was concentrated and the residue
was chromatographed (SiO.sub.2; 1-10% 2 M NH.sub.3 in MeOH/DCM) to
give the title compound (285 mg, 64%) as an oil. MS (ESI): mass
calcd. for C.sub.24H.sub.32FN.sub.3O.sub.5, 461.23; m/z found,
462.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.03 (s, 1H),
7.30-7.24 (m, 2H), 7.15-7.03 (m, 2H), 6.95 (s, 1H), 5.55 (t, 8.2,
1H), 5.43 (s, 1H), 5.02-4.92 (m, 2H), 4.34-4.27 (m 2H), 3.35 (s,
3H), 3.27 (s, 3H), 2.55-2.42 (m, 6H), 2.05-1.95 (m, 2H), 1.69-1.60
(m, 4H), 1.49-1.42 (m, 2H).
Step D. A solution of
1-(3-{3-dimethoxymethyl-4-[1-(2-fluoro-phenyl)-2-nitro-ethyl]-phenoxy}-pr-
opyl)-piperidine (280 mg, 0.607 mmol) in acetic acid (5 mL) was
treated with Zn powder (308 mg, 4.7 mmol), and the resulting
mixture was heated at 40.degree. C. for 16 h. The mixture was
cooled to 0.degree. C. and filtered, washing with MeOH. The
filtrated was concentrated, and the resulting oil was treated with
6 N HCl at 0.degree. C. for 3 d. The mixture was neutralized by the
slow addition of satd. aq. NaHCO.sub.3, and then was extracted with
DCM. The organic layer was dried and concentrated. The crude
material was chromatographed (SiO.sub.2; 1-10% 2 M NH.sub.3 in
MeOH/DCM) to give the title compound (60.9 mg, 27%) as an oil. MS
(ESI): mass calcd. for C.sub.22H.sub.28FN.sub.3O, 369.22; m/z
found, 370.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s, 1H),
7.26-7.17 (m, 1H), 7.10-7.00 (m, 2H), 6.88-6.80 (m, 1H), 6.47 (s,
1H), 4.41 (t, J=5.1, 1H), 4.27 (t, J=6.5, 1H), 4.08 (d, J=17.4,
1H), 4.01 (d, J=17.2, 1H), 3.34 (dd, J=13.2, 5.0, 1H), 3.14 (dd,
J=13.1, 5.7, 1H), 2.49-2.35 (m, 6H), 2.00-1.91 (m, 2H), 1.64-1.54
(m, 4H), 1.47-1.39 (m, 2H).
##STR00010##
Example 2
4-(2-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]-naphthyridine
A solution of
4-(2-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
naphthyridine (50.2 mg, 0.136 mmol) in MeOH (5 mL) was treated with
paraformaldehyde (62 mg). The mixture was heated at 55.degree. C.
for 1 h, cooled to 0.degree. C., and was treated with NaBH.sub.4
(66 mg, 1.74 mmol). After 2 h at 0.degree. C., the mixture was
diluted with satd. aq. NaHCO.sub.3 and extracted with DCM. The
organic layer was dried and concentrated. The residue was
chromatographed (SiO.sub.2; 1-10% 2 M NH.sub.3 in MeOH/DCM) to give
the title compound (20.4 mg, 39%) as an oil. MS (ESI): mass calcd.
for C.sub.23H.sub.30FN.sub.3O, 383.24; m/z found, 384.5
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.69 (s, 1H), 7.23-7.17 (m,
1H), 6.47 (s, 1H), 4.57-4.54 (m, 1H), 4.26 (t, J=6.7, 2H), 3.62 (d,
J=15.9, 1H), 3.58 (d, J=15.9, 1H), 2.97 (dd, J=12.0, 5.1, 1H), 2.65
(dd, J=11.5, 7.5, 1H), 2.47-2.36 (m, 9H), 1.98-1.91 (m, 2H),
1.61-1.55 (m, 4H), 1.47-1.39 (m, 2H).
##STR00011##
Example 3
2-Methyl-4-phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-na-
phthyridine
##STR00012##
Step A.
6-Methyl-8-phenyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-3-one. A
0.degree. C. solution of
7-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-[2,6]naphthyridine
(74.5 mg, 0.293 mmol) in CH.sub.3CN (1 mL) was treated with TMSCl
(1 mL) and NaI (.about.10 mg). The resulting mixture was stirred at
0.degree. C. for 30 min, then at 50.degree. C. for 18 h. The
mixture was concentrated, diluted with satd. aq. NaHCO.sub.3 and
extracted with DCM. The organic layer was dried and concentrated.
.sup.1H NMR indicated .about.30% conversion to the desired product.
The material was diluted with CH.sub.3CN (2 mL), treated with TMSCl
(1 mL) and NaI (.about.10 mg) and heated at 60.degree. C. for 18 h.
The mixture was concentrated, neutralized with satd. aq.
NaHCO.sub.3 and extracted with DCM. The organic layer was dried and
concentrated. The crude mixture was chromatographed (SiO.sub.2;
1-10% 2 M NH.sub.3 in MeOH/DCM) to give the title compound (29.6
mg, 42%). .sup.1H NMR (CDCl.sub.3): 7.33-7.23 (m, 3H), 7.20-7.16
(m, 2H), 6.83 (s, 1H), 6.26 (s, 1H), 4.06-4.00 (m, 1H), 3.73 (d,
J=15.9, 1H), 3.40 (d, J=15.2, 1H), 3.03-2.97 (m, 1H), 2.46 (dd,
J=11.6, 10.0, 1H), 2.41 (s, 3H).
Step B. A solution of
6-methyl-8-phenyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-3-one
(82.8 mg, 0.326 mmol) in DMF (3 mL) and THF (2 mL) was treated with
NaH (60% in oil; 62 mg). After 30 min, 1-chloro-3-iodopropane
(0.075 mL) was added. After 1 h at 0.degree. C., the mixture was
diluted with satd. aq. NaHCO.sub.3 and extracted with DCM. The
organic layer was washed with H.sub.2O (2.times.), dried, and
concentrated. The residue was diluted with n-butanol (5 mL) and
treated with piperidine (1.5 mL), Na.sub.2CO.sub.3 (150 mg), and KI
(.about.10 mg). After 18 h at 55.degree. C., the mixture was
cooled, concentrated, neutralized with satd. aq. NaHCO.sub.3, and
extracted with DCM. The organic layer was dried and concentrated.
Preparative TLC (SiO.sub.2; 10% 2 M NH.sub.3 in MeOH/DCM) gave the
title compound (2.5 mg, 2%). .sup.1H NMR (CDCl.sub.3): 7.34-7.19
(m, 5H), 6.84 (s, 1H), 6.31 (s, 1H), 4.05-4.00 (m, 1H), 3.88-3.82
(m, 2H), 3.66 (d, J=15.9, 1H), 3.40 (d, J=16.0, 1H), 2.99-2.93 (m,
1H), 2.46-2.40 (m, 1H), 2.39 (s, 3H), 2.55-2.06 (m, 6H), 1.87-1.74
(m, 2H), 1.46-1.33 (m, 6H).
6-Methyl-8-phenyl-2-(3-piperidin-1-yl-propyl)-5,6,7,8-tetrahydro-2H-[2,6]-
naphthyridin-3-one (22.6 mg, 19%) was also obtained. .sup.1H NMR
(CDCl.sub.3): 7.65 (s, 1H), 7.32-7.17 (m, 5H), 6.45 (s, 1H),
4.27-4.18 (m, 3H), 3.65 (d, J=15.7, 1H), 3.53 (d, J=15.6, 1H),
3.04-2.99 (m, 1H), 2.58-2.37 (m, 9H), 2.00-1.91 (m, 2H), 1.70-1.54
(m, 5H), 1.47-1.40 (m, 2H).
The compounds in Examples 4-47 were prepared by the methods
described above.
##STR00013##
Example 4
4-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridin-
e
MS (ESI): mass calcd. for C.sub.22H.sub.29N.sub.3O, 351.23; m/z
found, 352.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s, 1H),
7.33-7.20 (m, 3H) 7.11-7.07 (m, 2H), 6.46 (s, 1H), 4.27 (t, J=6.5,
2H), 4.11-3.99 (m, 3H), 3.36 (dd, J=13.9, 5.1, 1H), 3.08 (dd,
J=13.2, 6.3, 1H), 2.51-2.37 (m, 6H), 2.01-1.91 (m, 2H), 1.65-1.56
(m, 4H), 1.47-1.41 (m, 2H).
##STR00014##
Example 5
Diethyl-[3-(8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy)-propyl]-
-amine
MS (ESI): mass calcd. for C.sub.21H.sub.29N.sub.3O, 339.23; m/z
found, 340.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s, 1H),
7.32-7.21 (m, 2H), 7.11-7.07 (m, 2H), 6.46 (s, 1H), 4.26 (t, J=6.4,
2H), 4.12-3.99 (m, 3H), 3.36 (dd, J=13.3, 5.1, 1H), 3.08 (dd,
J=13.1, 6.5, 1H), 2.63-2.50 (m, 6H), 1.95-1.86 (m, 2H), 1.07-1.00
(m, 6H).
##STR00015##
Example 6
4-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.31N.sub.3O.sub.2, 381.24;
m/z found, 382.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s,
1H), 7.02-6.99 (m, 2H), 6.86-6.82 (m, 2H), 6.45 (s, 1H), 4.26 (t,
J=6.4, 2H), 4.10-3.97 (m, 3H), 3.79 (s, 3H), 3.32 (dd, J=13.1, 5.3,
1H), 3.04 (dd, J=13.1, 6.3, 1H), 2.50-2.35 (m, 7H), 1.99-1.91 (m,
2H), 1.48-1.40 (m, 2H).
##STR00016##
Example 7
Diethyl-[3-(6-methyl-8-phenyl-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy-
)-propyl]-amine
MS (ESI): mass calcd. for C.sub.22H.sub.31N.sub.3O, 353.25; m/z
found, 354.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.66 (s, 1H),
7.33-7.17 (m, 5H), 6.46 (s, 1H), 4.27-4.17 (m, 3H), 3.70 (d,
J=15.7, 1H), 3.53 (d, J=15.7, 1H), 3.04-2.94 (m, 1H), 2.06-2.05 (m,
7H), 2.41 (s, 3H), 1.93 (m, 2H), 1.02 (t, J=7.2, 6H).
##STR00017##
Example 8
4-(4-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.24H.sub.33N.sub.3O.sub.2, 395.26;
m/z found, 396.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.66 (s,
1H), 7.10 (d, J=8.8, 2H), 6.83 (d, J=8.8, 2H), 6.44 (s, 1H), 4.25
(t, J=6.5, 2H), 4.16 (dd, J=8.9, 5.9, 1H), 3.79 (s, 3H), 3.68 (d,
J=15.8, 1H), 3.51 (d, J=15.8, 1H), 2.98 (ddd, J=11.5, 5.6, 1.1,
1H), 2.53-2.35 (m, 10H), 1.98-1.90 (m, 2H), 1.61-1.38 (m, 4H),
1.46-1.38 (m, 2H).
##STR00018##
Example 9
4-(4-Methoxy-phenyl)-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2,3,4-tetra-
hydro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.29N.sub.3O.sub.2, 367.23;
m/z found, 368.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.72 (s,
1H), 7.01 (d, J=8.8, 2H), 6.84 (d, J=8.5, 2H), 6.45 (s, 1H),
4.34-4.22 (m, 2H), 4.11-3.97 (m, 3H), 3.79 (s, 3H), 3.32 (dd,
J=13.0, 5.0, 1H), 3.10-3.02 (m, 2H), 2.34 (s, 3H), 2.23-2.10 (m,
3H), 2.05-1.95 (m, 1H), 1.85-1.49 (m, 5H).
##STR00019##
Example 10
4-(4-Methoxy-phenyl)-2-methyl-7-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1,2,-
3,4-tetrahydro-[2,6]-naphthyridine
.sup.1H NMR (CDCl.sub.3): 7.60 (s, 1H), 7.03 (d, J=8.8, 1H), 6.76
(d, J=8.9, 2H), 6.37 (s, 1H), 4.26-4.05 (m, 3H), 3.72 (s, 3H), 3.62
(d, J=15.6, 1H), 3.44 (d, J=15.6, 1H), 3.03-2.96 (m, 1H), 2.91
(ddd, J=11.6, 5.5, 1.2, 1H), 2.43 (dd, J=11.6, 8.8, 1H), 2.34 (s,
3H), 2.27-2.25 (m, 3H), 1.96-1.87 (m, 1H), 1.76-1.41 (m, 4H).
##STR00020##
Example 11
4-(4-Methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
-naphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.29N.sub.3O.sub.3, 383.2;
m/z found, 384.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.74 (s,
1H), 7.07-7.01 (m, 2H), 6.90-6.85 (m, 2H), 6.48 (s, 1H), 4.32 (t,
J=6.5, 2H), 4.14-3.97 (m, 3H), 3.82 (s, 3H), 3.75 (t, J=4.7, 4H),
3.39-3.31 (m, 1H), 3.12-3.04 (m, 1H), 2.59-2.21 (m, 7H), 2.21-2.05
(br s, 1H), 2.03-2.93 (m, 2H).
##STR00021##
Example 12
4-(4-Methoxy-phenyl)-2-methyl-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.31N.sub.3O.sub.3, 397.2;
m/z found, 398.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.59 (s,
1H), 7.05-7.01 (m, 2H), 6.89-6.74 (m, 2H), 6.80-6.74 (m, 2H), 6.37
(s, 1H), 4.21 (t, J=4.5, 2H), 4.12-4.05 (m, 1H), 3.72 (s, 3H),
3.69-3.58 (m, 6H), 3.48-3.40 (m, 1H), 2.95-2.88 (m, 1H), 2.49-2.36
(m, 8H), 2.34 (s, 3H), 1.95-1.82 (m, 3H).
##STR00022##
Example 13
4-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]-
-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.31N.sub.3O.sub.2, 381.24;
m/z found, 382.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.65 (s,
1H), 7.15 (dd, J=7.9, 7.9, 1H), 6.71-6.68 (m, 1H), 6.55-6.54 (m,
1H), 6.37 (s, 1H), 4.19 (t, J=6.4, 2H), 4.02-3.90 (m, 3H), 3.70 (s,
3H), 3.27 (dd, J=13.2, 5.2, 1H), 3.02 (dd, J=13.3, 6.1, 1H),
2.49-2.31 (m, 6H), 1.95-1.87 (m, 2H), 1.58-1.52 (m, 4H), 1.42-1.33
(m, 2H).
##STR00023##
Example 14
4-(3-Methoxy-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine
.sup.1H NMR (CDCl.sub.3): 7.61 (s, 1H), 7.14 (t, J=7.9, 1H),
6.74-6.65 (m, 3H), 6.37 (s, 1H), 4.18 (t, J=6.5, 2H), 4.10 (dd,
J=8.6, 5.6, 1H), 3.70 (s, 3H), 3.61 (d, J=15.9, 1H), 3.45 (d,
J=15.7, 1H), 2.92 (ddd, J=11.6, 5.5, 1.3, 1H), 2.48 (dd, J=11.5,
8.8, 1H), 2.43-2.29 (m, 9H), 1.92-1.85 (m, 2H), 1.56-1.50 (m, 4H),
1.41-1.33 (m, 2H).
##STR00024##
Example 15
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2-
,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.27Cl.sub.2N.sub.3O, 419.2;
m/z found, 420.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.61 (s,
1H), 7.30 (d, J=8.2, 1H), 7.13-7.11 (m, 1H), 6.91-6.86 (m, 1H),
6.39 (s, 1H), 4.20 (t, J=6.5, 2H), 4.04-3.88 (m, 3H), 3.40 (s, 1H),
3.27 (dd, J=12.9, 5.1, 1H), 2.96 (dd, J=12.9, 6.1, 1H), 2.64-2.45
(m, 8H), 1.96-1.84 (m, 3H), 1.42-1.30 (m, 3H).
##STR00025##
Example 16
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetr-
ahydro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.29Cl.sub.2N.sub.3O, 433.2;
m/z found, 434.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.59 (s,
1H), 7.28 (d, J=8.4, 1H), 7.25-7.21 (m, 1H), 6.96 (dd, J=8.2, 2.2,
1H), 7.20 (s, 1H), 4.19 (t, J=6.5, 2H), 4.07 (t, J=6.3, 1H), 3.52
(s, 2H), 2.85 (dd, J=11.5, 5.3, 1H), 2.53-2.45 (m, 1H), 2.42-2.28
(m, 9H), 1.94-1.81 (m, 3H), 1.57-1.47 (m, 4H), 1.41-1.30 (m, 2H),
1.25-1.11 (m, 1H).
##STR00026##
Example 17
4-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.28FN.sub.3O, 369.22; m/z
found, 370.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.68 (s, 1H),
7.08-6.93 (m, 4H), 6.46 (s, 1H), 4.26 (t, J=6.4, 2H), 4.10-3.98 (m,
4H), 3.35 (dd, J=13.1, 5.0, 1H), 3.03 (dd, J=13.1, 6.3, 1H),
2.50-2.33 (m, 6H), 2.00-1.90 (m, 2H), 1.63-1.55 (m, 4H), 1.48-1.40
(m, 2H).
##STR00027##
Example 18
4-(4-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.30FN.sub.3O, 383.24; m/z
found, 384.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.65 (s, 1H),
7.17-7.13 (m, 2H), 7.00-6.95 (m, 2H), 6.45 (s, 1H), 4.26 (t, J=6.6,
2H), 4.20-4.17 (m, 1H), 3.66 (d, J=15.8, 1H), 3.54 (d, J=15.8, 1H),
2.97 (ddd, J=11.5, 5.5, 1.2, 1H), 2.52 (dd, J=11.5, 8.2, 1H),
2.47-2.36 (m, 9H), 1.99-1.91 (m, 2H), 1.62-1.54 (m, 4H), 1.47-1.39
(m, 2H).
##STR00028##
Example 19
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-1,2,3,4-t-
etrahydro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.29F.sub.2N.sub.3O.sub.2,
417.2; m/z found, 418.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71
(s, 1H), 7.05-6.96 (m, 2H), 6.88-6.78 (m, 2H), 6.44 (s, 1H),
4.32-4.24 (m, 2H), 4.13-3.95 (m, 3H), 3.79 (s, 3H), 3.37-3.28 (m,
1H), 3.09-3.00 (m, 1H), 2.62-2.48 (m, 6H), 2.07-1.88 (m, 6H).
##STR00029##
Example 20
Diethyl-{3-[8-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yl-
oxy]-propyl}-amine
MS (ESI): mass calcd. for C.sub.22H.sub.31N.sub.3O.sub.2, 369.2;
m/z found, 370.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s,
1H), 7.07-6.96 (m, 2H), 6.90-6.77 (m, 2H), 6.45 (s, 1H), 4.35-4.20
(m, 2H), 4.12-3.95 (m, 3H), 3.79 (s, 3H), 3.36-3.28 (m, 1H),
3.09-2.99 (m, 1H), 2.69-2.45 (m, 6H), 1.98-1.85 (m, 2H), 1.09-0.97
(m, 6H).
##STR00030##
Example 21
{3-[8-(3,4-Dichloro-phenyl)-5,6,7,8-tetrahydro-[2,6]naphthyridin-3-yloxy]--
propyl}-diethyl-amine
MS (ESI): mass calcd. for C.sub.21H.sub.27Cl.sub.2N.sub.3O, 407.2;
m/z found, 408.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.69 (s,
1H), 7.40-7.34 (m, 1H), 7.21-7.19 (m, 1H), 6.99-6.93 (m, 1H), 6.47
(s, 1H), 4.27 (t, J=6.5, 2H), 1.12-3.97 (m, 3H), 3.35 (dd, J=12.9,
5.3, 1H), 3.04 (dd, J=12.9, 6.1, 1H), 2.65-2.48 (m, 6H), 1.96-1.85
(m, 2H), 1.07-0.98 (m, 6H).
##STR00031##
Example 22
7-(1-Benzyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydro-[2,-
6]-naphthyridine
MS (ESI): mass calcd. for C.sub.27H.sub.31N.sub.3O.sub.2, 429.24;
m/z found, 430.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.69 (s,
1H), 7.34-7.28 (m, 5H), 7.01 (d, J=8.4, 2H), 6.84 (d, J=8.8, 2H),
6.44 (s, 1H), 5.02-4.94 (m, 1H), 4.08-3.96 (m, 3H), 3.79 9s, 3H),
3.52 (s, 2H), 3.31 (dd, J=12.9, 5.0, 1H), 3.03 (dd, J=12.9, 6.5,
1H), 2.78-2.70 (m, 2H), 2.33-2.25 (m, 2H), 2.06-1.96 (m, 2H),
1.85-1.75 (m, 2H).
##STR00032##
Example 23
4-(4-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.28ClN.sub.3O, 385.19; m/z
found, 386.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.68 (s, 1H),
7.27 (d, J=8.7, 2H), 7.03 (d, J=8.4, 2H), 6.46 (s, 1H), 4.26 (t,
J=6.6, 2H), 4.10-3.98 (m, 3H), 3.34 (dd, J=13.3, 4.9, 1H), 3.03
(dd, J=12.9, 6.5, 1H), 2.48-2.35 (m, 6H), 2.00-1.91 (m, 2H),
1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).
##STR00033##
Example 24
4-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.28ClN.sub.3O, 385.19; m/z
found, 386.5 [M+H].sup.+.
##STR00034##
Example 25
4-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
##STR00035##
Example 26
4-(3,4-Dichloro-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-[2-
,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.21H.sub.25Cl.sub.2N.sub.3O.sub.2,
421.1; m/z found, 422.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.69
(s, 1H), 7.40-7.34 (m, 1H), 7.21-7.18 (m, 1H), 6.99-6.94 (m, 1H),
6.47 (s, 1H), 4.30 (t, J=6.5, 2H), 4.12-3.97 (m, 3H), 3.75-3.67 (m,
4H), 3.35 (dd, J=12.9, 5.3, 1H), 3.04 (dd, J=12.9, 6.1, 1H),
2.55-2.39 (m, 6H), 2.01-1.89 (m, 2H).
##STR00036##
Example 27
4-(3-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.30ClN.sub.3O, 399.21; m/z
found, 400.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.66 (s, 1H),
7.25-7.18 (m, 3H), 7.10-7.06 (m, 1H), 6.46 (s, 1H), 4.26 (t, J=6.5,
2H), 4.19-4.15 (m, 1H), 3.64 (d, J=15.7, 1H), 3.56 (d, J=15.7, 1H),
3.00-2.94 (m, 1H), 2.55 (dd, J=11.7, 8.0, 1H), 2.48-2.38 (m, 8H),
2.00-1.91 (m, 2H), 1.61-1.56 (m, 4H), 1.47-1.40 (m, 2H).
##STR00037##
Example 28
7-[3-(4,4-Difluoro-piperidin-1-yl)-propoxy]-4-(4-methoxy-phenyl)-2-methyl--
1,2,3,4-tetrahydro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.24H.sub.31F.sub.2N.sub.3O.sub.2,
431.2; m/z found, 432.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.67
(s 1H), 7.14-7.06 (m, 2H), 6.86-6.81 (m, 2H), 6.44 (s, 1H), 4.27
(t, J=6.5, 2H), 4.16 (dd, J=8.4, 5.5, 1H), 3.79 (s, 3H), 3.72-3.65
(m, 1H), 3.48-3.44 (m, 1H), 3.01-2.95 (m, 1H), 2.61-2.47 (m, 7H),
2.41 (s, 3H), 2.06-1.88 (m, 6H).
##STR00038##
Example 29
Diethyl-{3-[8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthyr-
idin-3-yloxy]-propyl}-amine
MS (ESI): mass calcd. for C.sub.23H.sub.33N.sub.3O.sub.2, 383.3;
m/z found, 384.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.67 (s,
1H), 7.14-7.08 (m, 2H), 6.86-6.81 (m, 2H), 6.44 (s, 1H), 4.86-4.23
(m, 2H), 4.18-4.13 (m, 1H), 3.79 (s, 3H), 3.69 (d, J=15.8, 1H),
3.52 (d, J=15.6, 1H), 3.01-2.95 (m, 1H), 2.70-2.46 (m, 7H), 2.41
(s, 3H), 1.98-1.88 (m, 2H), 1.10-1.00 (m, 6H).
##STR00039##
Example 30
{3-[8-(3,4-Dichloro-phenyl)-6-methyl-5,6,7,8-tetrahydro-[2,6]naphthyridin--
3-yloxy]-propyl}-diethyl-amine
MS (ESI): mass calcd. for C.sub.22H.sub.29Cl.sub.2N.sub.3O, 421.2;
m/z found, 422.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71-7.61
(m, 1H), 7.50-7.40 (m, 1H), 7.34-7.27 (m, 1H), 7.13-7.01 (m, 1H),
6.63-6.54 (m, 1H), 4.71-4.24 (m, 6H), 3.82-3.64 (m, 2H), 3.33-3.07
(m, 8H), 2.49-2.12 (m, 2H), 1.41-1.21 (m, 6H).
##STR00040##
Example 31
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-1,2,3,4-tetrahy-
dro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.24H.sub.33N.sub.3O.sub.2, 395.3;
m/z found, 396.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.71 (s,
1H), 7.05-6.96 (m, 2H), 6.88-6.81 (m, 2H), 6.45 (s, 1H), 4.13-3.95
(m, 5H), 3.79 (s, 3H), 3.32 (dd, J=12.9, 5.1, 1H), 3.04 (dd,
J=12.9, 6.3, 1H), 2.95-2.88 (m, 2H), 2.76-2.66 (m, 1H), 2.20-2.09
(m, 2H), 1.92-1.70 (m, 4H), 1.46-1.32 (m, 2H), 1.09-1.01 (m,
6H).
##STR00041##
Example 32
4-(3-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]n-
aphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.28FN.sub.3O, 369.22; m/z
found, 370.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.70 (s, 1H),
7.29-7.23 (m, 1H), 6.95-6.88 (m, 2H), 6.80-6.76 (m, 1H), 6.46 (s,
1H), 4.27 (t, J=6.4, 2H), 4.10-3.98 (m, 3H), 3.35 (dd, J=13.0, 5.1,
1H), 3.07 (dd, J=13.0, 6.1, 1H), 2.50-2.31 (m, 5H), 1.99-1.89 (m,
2H), 1.62-1.55 (m, 4H), 1.46-1.40 (m, 2H).
##STR00042##
Example 33
4-(3-Chloro-4-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.27ClFN.sub.3O, 403.18; m/z
found, 404.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.68 (s, 1H),
7.13 (dd, J=7.1, 2.2, 1H), 7.07 (dd, J=8.6, 8.5, 1H), 7.00-6.95 (m,
1H), 6.47 (s, 1H), 4.27 (t, J=6.4, 2H), 4.10-3.97 (m, 3H), 3.34
(dd, J=12.9, 5.1, 1H), 3.03 (dd, J=12.9, 6.3, 1H), 2.49-2.36 (m,
6H), 2.00-1.92 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).
##STR00043##
Example 34
4-(3-Fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.30FN.sub.3O, 383.24; m/z
found, 384.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.67 (s, 1H),
7.28-7.22 (m, 1H), 7.00-6.98 (m, 1H), 6.94-6.88 (m, 2H), 6.45 (s,
1H), 4.29 (t, J=6.6, 2H), 4.21-4.17 (m, 1H), 3.64 (d, J=15.7, 1H),
3.57 (d, J=16.0, 1H), 3.00-2.96 (m, 1H), 2.67-2.46 (m, 5H), 2.41
(s, 3H), 2.10-2.01 (m, 2H), 1.77-1.43 (m, 8H).
##STR00044##
Example 35
4-(3-Chloro-4-fluoro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-
-tetrahydro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.29ClFN.sub.3O, 417.20; m/z
found, 418.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.65 (s, 1H),
7.25-7.22 (m, 1H), 7.07-7.04 (m, 2H), 6.46 (s, 1H), 4.27 (d, J=6.4,
2H), 4.16-4.13 (m, 1H), 3.65-3.55 (m, 2H), 2.93 (dd, J=11.5, 5.5,
1H), 2.60-2.40 (m, 6H), 2.40 (s, 3H), 2.04-1.96 (m, 2H), 1.72-1.52
(m, 8H).
##STR00045##
Example 36
4-(4-Chloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahyd-
ro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.30ClN.sub.3O, 399.21; m/z
found, 400.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.64 (s, 1H),
7.26 (d, J=8.6, 2H), 7.13 (d, J=8.3, 2H), 6.45 (s, 1H), 4.25 (t,
J=6.2, 2H), 4.18-4.15 (m, 1H), 3.65 (d, J=15.9, 1H), 3.56 (d,
J=15.6, 1H), 2.97-2.93 (m, 1H), 2.53 (dd, J=11.5, 7.9, 1H),
2.50-2.38 (m, 9H), 1.99-1.92 (m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40
(m, 2H).
##STR00046##
Example 37
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-1,2,3,4-tetr-
ahydro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.24H.sub.33N.sub.3O.sub.2, 395.3;
m/z found, 396.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.68 (s,
1H), 7.39-7.34 (m, 1H), 7.21-7.19 (m, 1H), 6.96 (dd, J=8.2, 2.2,
1H), 6.47 (s, 1H), 4.12-3.97 (m, 5H), 3.34 (dd, J=12.9, 5.1, 1H),
3.04 (dd, J=12.9, 6.1, 1H), 2.97-2.88 (m, 2H), 2.77-2.68 (m, 1H),
2.21-2.11 (m, 2H), 1.89-1.71 (m, 4H), 1.47-1.33 (m, 2H), 1.11-1.00
(m, 6H).
##STR00047##
Example 38
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetr-
ahydro-[2,6]-naphthyridine (enantiomer A).
Racemic
4-(3,4-dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2-
,3,4-tetrahydro-[2,6]-naphthyridine (Example 16) was separated into
enantiomers by chiral HPLC (Conditions: AD-H 30% MeOH/Et.sub.3N,
100 bar, 30.degree. C., 3 mL/min). R.sub.T=3.7 min.
##STR00048##
Example 39
4-(3,4-Dichloro-phenyl)-2-methyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetr-
ahydro-[2,6]-naphthyridine (enantiomer B)
This compound was obtained as described in Example 38. R.sub.T=6.2
min.
##STR00049##
Example 40
7-(1-Isopropyl-piperidin-4-ylmethoxy)-4-(4-methoxy-phenyl)-2-methyl-1,2,3,-
4-tetrahydro-[2,6]-naphthyridine
MS (ESI): mass calcd. for C.sub.25H.sub.35N.sub.3O.sub.2, 409.3;
m/z found, 410.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.72 (s,
1H), 7.15-7.08 (m, 2H), 6.93-6.87 (m, 2H), 6.53 (s, 1H), 4.93-4.41
(m, 2H), 4.40-4.04 (m, 4H), 3.81 (s, 3H), 3.79-3.65 (m, 1H),
3.61-3.45 (m, 3H), 2.99 (s, 3H), 2.84-2.66 (m, 2H), 2.14-1.89 (m,
5H), 1.49-1.20 (m, 6H).
##STR00050##
Example 41
4-(3,4-Dichloro-phenyl)-7-(1-isopropyl-piperidin-4-ylmethoxy)-2-methyl-1,2-
,3,4-tetrahydro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.24H.sub.31Cl.sub.2N.sub.3O, 447.2;
m/z found, 448.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.72 (s,
1H), 7.53-7.43 (m, 1H), 7.32-7.28 (m, 1H), 7.12-7.06 (m, 1H), 6.57
(s, 1H), 4.75-4.50 (m, 2H), 4.35-4.10 (m, 3H), 3.87-3.71 (m, 1H),
3.61-3.48 (m, 3H), 3.25-3.05 (m, 1H), 3.00 (s, 3H), 2.10-1.78 (m,
5H), 1.44-1.28 (m, 6H).
##STR00051##
Example 42
4-(4-Methoxy-phenyl)-7-(piperidin-4-yloxy)-1,2,3,4-tetrahydro-[2,6]naphthy-
ridine
MS (ESI): mass calcd. for C.sub.20H.sub.25N.sub.3O.sub.2, 339.19;
m/z found, 340.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.69 (s,
1H), 7.01 (d, J=8.6, 2H), 6.84 (d, J=8.7, 2H), 6.44 (s, 1H),
5.13-5.01 (m, 1H), 4.11-3.96 (m, 3H), 3.79 (s, 3H), 3.36-3.28 (m,
1H), 3.15-3.00 (m, 3H), 2.81-2.69 (m, 2H), 2.08-1.94 (m, 3H),
1.70-1.57 (m, 3H).
##STR00052##
Example 43
4-(4-Methoxy-phenyl)-2-methyl-7-(1-methyl-piperidin-4-yloxy)-1,2,3,4-tetra-
hydro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.22H.sub.29N.sub.3O.sub.2, 367.26;
m/z found, 368.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.65 (s,
1H), 7.11 (d, J=8.5, 2H), 6.83 (d, J=8.9, 2H), 6.44 (s, 1H),
5.01-4.94 (m, 1H), 4.15 (dd, J=8.6, 5.6, 1H), 3.79 (s, 3H), 3.68
(d, J=16.0, 1H), 3.50 (d, J=15.5, 1H), 2.98 (ddd, J=11.6, 5.5, 1.2,
1H), 2.76-2.66 (m, 2H), 2.51 (dd, J=11.6, 8.9, 1H), 2.41 (s, 3H),
2.33-2.25 (m, 5H), 2.06-1.99 (m, 2H), 1.86-1.76 (m, 2H).
##STR00053##
Example 44
7-(3-Piperidin-1-yl-propoxy)-4-(4-trifluoromethoxy-phenyl)-1,2,3,4-tetrahy-
dro-[2,6]naphthyridine
MS (ESI): mass calcd. for C.sub.23H.sub.28F.sub.3N.sub.3O.sub.2,
435.2; m/z found, 436.5 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.60
(s, 1H), 7.13-7.02 (m, 4H), 6.39 (s, 1H), 4.2 (t, J=6.5, 2H),
4.05-3.90 (m, 3H), 3.29 (dd, J=12.9, 5.1, 1H), 2.98 (dd, J=12.9,
6.3, 1H), 2.50-2.26 (m, 6H), 1.98-1.86 (m, 2H), 1.61-1.50 (m, 5H),
1.28-1.14 (m, 1H).
##STR00054##
Example 45
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2-
,6]-naphthyridine (enantiomer A)
Racemic
4-(3,4-dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetr-
ahydro-[2,6]-naphthyridine (Example 15) was separated into
enantiomers by chiral HPLC (Conditions: OD 25% MeOH/Et.sub.3N, 100
bar, 30.degree. C., 2 mL/min). R.sub.T=12.7 min.
##STR00055##
Example 46
4-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2-
,6]-naphthyridine (enantiomer B)
This compound was obtained as described in Example 45. R.sub.T=18.5
min.
##STR00056##
Example 47
7-(3-Morpholin-4-yl-propoxy)-4-phenyl-1,2,3,4-tetrahydro-[2,6]naphthyridin-
e
MS (ESI): mass calcd. for C.sub.21H.sub.27N.sub.3O.sub.2, 353.21;
m/z found, 354.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.70 (s,
1H), 7.31-7.27 (m, 2H), 7.24-7.20 (m, 1H), 7.08 (d, J=7.1, 1H),
6.45 (s, 1H), 4.28 (t, J=6.7, 2H), 4.01-3.98 (m, 3H), 3.71-3.69 (m,
4H), 3.35 (dd, J=13.3, 5.2, 1H), 3.08 (dd, J=13.2, 6.3, 1H),
2.51-2.42 (m, 7H), 1.96-1.90 (m, 2H).
##STR00057##
Example 48
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tetr-
ahydro-[1,6]naphthyridine trifluoroacetic acid salt
##STR00058##
Step A. 5-Bromo-2-hydroxy-nicotinic acid. To a 0.degree. C.
solution of 50% aq. NaOH (45.4 g) and H.sub.2O (251 mL) was added
Br.sub.2 (10 mL) dropwise over 5 min, additional 50% aq. NaOH (59.3
g), and 2-hydroxy-nicotinic acid (33.4 g). The resulting dark green
solution was heated at 50.degree. C. for 18 h, then was cooled to
0.degree. C. and treated slowly with 12.1 N HCl until a solid
precipitated. The solid was collected by vacuum filtration and
dried under vacuum to give a white solid (40.8 g, 78%), which was
taken on to the next step without purification. MS (ESI): mass
calcd. for C.sub.6H.sub.4BrNO.sub.3, 216.94; m/z found, 218.2
[M+H].sup.+. .sup.1H NMR (DMSO-d.sub.6): 14.33 (br s, 1H), 13.80
(br s, 1H), 8.37 (s, 1H), 8.30 (s, 1H).
##STR00059##
Step B. 5-Bromo-2-chloro-nicotinic acid. A mixture of
5-bromo-2-hydroxy-nictonic acid (32.9 g, 0.151 mol), SOCl.sub.2
(167 mL), and DMF (10.5 mL) was heated at 70.degree. C. for 4 h.
The mixture was concentrated, cooled to 0.degree. C., and quenched
slowly with H.sub.2O to give an off-white precipitate. The
precipitate was stirred in H.sub.2O for 1 h, and then was collected
by filtration and dried under vacuum to give the title compound
(35.5 g, 99%). The product was carried on to the next step without
purification, but alternatively may be recrystallized from hot
H.sub.2O. MS (ESI): mass calcd. for C.sub.6H.sub.3BrClNO.sub.2,
234.90; m/z found, 236.2 [M+H].sup.+. .sup.1H NMR
(acetone-d.sub.6): 8.66 (d, J=2.5, 1H), 8.43 (d, J=2.5, 1H).
##STR00060##
Step C. (5-Bromo-2-chloro-pyridin-3-yl)-methanol. A 0.degree. C.
mixture of 5-bromo-2-chloro-nicotinic acid (10.0 g, 42.3 mmol) and
Et.sub.3N (50.8 mmol) in THF (440 mL) was treated with isobutyl
chloroformate (6.7 mL, 51 mmol). After 75 min, the mixture was
filtered. The filtrate was concentrated to approximately 220 mL,
diluted with H.sub.2O, cooled to 0.degree. C., and treated with
NaBH.sub.4 (3.38 g). After 2 h, the mixture was allowed to warm to
rt and was stirred for 18 h. The mixture was diluted with EtOAc,
washed with H.sub.2O (3.times.), brine, dried (K.sub.2CO.sub.3),
and concentrated to give an off-white solid. Chromatographic
purification (SiO.sub.2; EtOAc/hexanes) gave the title compound
(6.61 g, 70%) as a white solid. MS (ESI): mass calcd. for
C.sub.6H.sub.5BrClNO, 220.92; m/z found, 222.2 [M+H].sup.+. .sup.1H
NMR (acetone-d.sub.6): 8.38 (d, J=2.5, 1H), 8.12 (m, 1H), 4.82
(brs, 1H), 4.69 (s, 2H).
##STR00061##
Step D. Methanesulfonic acid 5-bromo-2-chloro-pyridin-3-ylmethyl
ester. A 0.degree. C. mixture of
(5-bromo-2-chloro-pyridin-3-yl)-methanol (1.00 g, 4.50 mmol) and
DIPEA (2.40 mL, 13.5 mmol) in THF (22 mL) was treated with
methanesulfonyl chloride (0.35 mL, 4.50 mmol). After 50 min, the
mixture was diluted with DCM, washed with H.sub.2O, satd. aq.
NaHCO.sub.3, and brine. The organic layer was dried (MgSO.sub.4)
and concentrated to give the title compound (1.47 g, >100%) as a
yellow oil.
##STR00062##
Step E. (5-Bromo-2-chloro-pyridin-3-ylmethyl)-methyl-amine. A
solution of methanesulfonic acid
5-bromo-2-chloro-pyridiny-3-ylmethyl ester (6.84 g, 22.8 mmol) in
EtOH (225 mL) was treated with MeNH.sub.2 (40% in H.sub.2O; 10 mL,
0.114 mol). After 2 h at rt, the mixture was concentrated and the
residue was triturated with DCM. The mixture was filtered, and the
filtrate was concentrated. The residue was chromatographed
(SiO.sub.2; EtOAc/hexanes) to give the title compound (3.23 g, 13.7
mmol) as a yellow oil. MS (ESI): mass calcd. for
C.sub.7H.sub.8BrClN.sub.2, 233.96; m/z found, 235.2 [M+H].sup.+.
.sup.1H NMR (CD.sub.3OD): 8.34 (d, J=2.4, 1H), 8.04 (d, J=2.4, 1H),
4.8 (br s, 1H), 3.78 (s, 2H), 2.41 (s, 3H).
##STR00063##
Step F.
N-(5-Bromo-2-chloro-pyridin-3-ylmethyl)-2-(4-methoxy-phenyl)-N-me-
thyl-acetamide. A 0.degree. C. solution of
(5-bromo-2-chloro-pyridin-3-ylmethyl)-methyl-amine (3.07 g, 13.0
mmol) and N-methylmorpholine (4.40 mL, 39.1 mmol) in DCM (130 mL)
was treated with (4-methoxy-phenyl)-acetyl chloride (2.40 mL, 15.6
mmol) dropwise over 4 min. The resulting bright yellow solution was
allowed to warm to rt and was stirred for 18 h. The mixture was
diluted with DCM, washed with H.sub.2O (2.times.), brine, dried
(MgSO.sub.4), and concentrated to a yellow oil. Chromatographic
purification (SiO.sub.2; EtOAc/hexanes) gave the title compound
(4.71 g, 94%) as a pale-yellow oil. MS (ESI): mass calcd. for
C.sub.16H.sub.16BrClN.sub.2O.sub.2, 382.01; m/z found, 383.3
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6, mixture of rotamers):
8.36 (d, J=2.3, 0.75H), 8.32 (d, J=2.1, 0.25H), 7.59-7.58 (m,
0.75H), 7.25-7.23 (m, 1.75H), 7.11 (d, J=8.5, 0.5H), 6.92-6.89 (m,
1.5H), 6.73 (d, J=8.6, 0.5H), 4.70 (s, 0.5H), 4.61 (s, 1.5H),
3.80-3.72 (m, 5H), 3.16 (s, 2.25H), 2.93 (s, 0.75H).
##STR00064##
Step G.
3-Bromo-8-(4-methoxy-phenyl)-6-methyl-5,8-dihydro-6H-[1,6]naphthy-
ridin-7-one. A slurry of NaH (95%; 530 mg, 17.3 mmol) in DMSO (3
mL) was treated with a solution of
N-(5-bromo-2-chloro-pyridin-3-ylmethyl)-2-(4-methoxy-phenyl)-N-methyl-ace-
tamide (2.21 g, 5.77 mmol) in DMSO (50 mL) over 5 min. After 2 h,
the mixture was diluted with H.sub.2O and extracted with EtOAc. The
organic layer was washed with H.sub.2O (3.times.), brine, dried
(MgSO.sub.4), and concentrated. The residue was purified
(SiO.sub.2; EtOH/hexanes) to give the title compound (1.30 g, 65%)
as a reddish-tan foam. MS (ESI): mass calcd. for
C.sub.16H.sub.15BrN.sub.2O.sub.2, 346.03; m/z found, 347.3
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 8.57 (d, J=1.9, 1H),
7.99-7.98 (m, 1H), 7.06-7.04 (m, 2H), 6.82-6.80 (m, 2H), 4.76 (d,
J=16.8, 1H), 4.53 (d, J=16.8, 1H), 3.73 (s, 3H), 3.07 (s, 3H).
##STR00065##
Step H.
3-Bromo-8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-[1,6]nap-
hthyridine. A solution of
3-bromo-8-(4-methoxy-phenyl)-6-methyl-5,8-dihydro-6H-[1,6]naphthyridin-7--
one (212 mg, 0.611 mmol) in THF (6.25 mL) was treated with
BH.sub.3.THF (1 M in THF; 2.0 mL). The mixture was heated at
60.degree. C. for 2 h, then was allowed to cool to rt and was
stirred for 18 h. The reaction was quenched by the slow addition of
H.sub.2O (5 mL) and conc. HCl (5 mL), and the resulting mixture was
heated at 70.degree. C. for 1 h. The mixture was cooled to rt,
neutralized with 1 N NaOH to pH.about.10, and extracted with DCM.
The organic layer was washed with H.sub.2O, brine, dried
(K.sub.2CO.sub.3), and concentrated. The residue was purified
(SiO.sub.2; EtOH/hexanes) to give the title compound (144 mg, 71%)
as a colorless oil. Further purification by preparative reverse
phase HPLC gave the product as the TFA salt. MS (ESI): mass calcd.
for C.sub.1-6H.sub.17BrN.sub.2O, 332.05; m/z found, 333.3
[M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 8.52 (s, 1H), 7.97 (d,
J=2.0, 1H), 7.07 (d, J=8.6, 2H), 6.92-6.90 (m, 2H), 4.93 (s, 2.5H),
4.69-4.56 (m, 3H), 3.94-3.90 (m, 1H), 3.79 (s, 3H), 3.65-3.61 (m,
1H), 3.08 (s, 3H).
Step I. A Smith process vial containing
3-bromo-8-(4-methoxy-phenyl)-6-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridi-
ne (81.6 mg, 0.245 mmol), PPh.sub.3 (22.6 mg, 0.086 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (3.7 mg, 0.0053 mmol), CuI (18.7 mg,
0.098 mmol), 1-but-3-ynyl-piperidine (208.6 mg, 1.52 mmol), and
Et.sub.2NH (1.0 mL) in DMF (1 mL) was purged with N.sub.2. The
mixture was heated at 120.degree. C. for 75 min, and then was
allowed to cool to rt. The mixture was diluted with EtOAc, washed
with H.sub.2O (3.times.), brine, dried (K.sub.2CO.sub.3), and
concentrated to give a reddish-brown oil. Chromatographic
purification (SiO.sub.2; 0-8% 2 N NH.sub.3 in MeOH/DCM) gave a pale
yellow oil, which was further purified by preparative reverse-phase
HPLC to give 102.0 mg (67%) of the product as the TFA salt. MS
(ESI): mass calcd. for C.sub.25H.sub.31N.sub.3O, 389.25; m/z found,
390.5 [M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 8.45 (s, 1H), 7.79 (s,
1H), 7.07 (d, J=8.6, 2H), 6.91-6.90 (m, 2H), 4.92 (s, 5H),
4.67-4.61 (m, 3H), 3.94-3.90 (m, 1H), 3.77 (s, 3H), 3.65-3.60 (m,
3H), 3.39 (t, J=7.3, 2H), 3.08 (s, 3H), 3.03-2.99 (m, 4H),
1.97-1.94 (m, 2H), 1.81-1.75 (m, 3H), 1.53-1.51 (m, 1H).
##STR00066##
Example 49
8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-butyl)-5,6,7,8-tetrahydr-
o-[1,6]-naphthyridine trifluoroacetic acid salt
A flask containing a mixture of
8-(4-methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tet-
rahydro-[1,6]naphthyridine (71.7 mg) and Pd/BaSO.sub.4 (101.3 mg)
in EtOH (5 mL) was evacuated and back-filled with N.sub.2
(3.times.) and then with H.sub.2 (3.times.). The mixture was
treated with H.sub.2 under balloon pressure for 4 h, then was
filtered through a pad of diatomaceous earth. The filtrate was
concentrated to give the title compound (47.3 mg, 96%). Treatment
with TFA gave the TFA salt. MS (ESI): mass calcd. for
C.sub.25H.sub.35N.sub.3O, 393.28; m/z found, 394.5 [M+H].sup.+.
.sup.1H NMR (CD.sub.3OD): 8.34 (s, 1H), 7.75 (s, 1H), 7.09 (d,
J=8.6, 2H), 6.91 (d, 8.7, 2H), 4.90 (s, 6H), 4.70-4.64 (m, 3H),
3.94-3.90 (m, 1H), 3.77 (s, 3H), 3.64-3.58 (m, 1H), 3.53-3.50 (br
m, 2H), 3.12-3.09 (m, 2H), 3.10 (s, 3H), 2.94-2.87 (m, 2H), 2.76
(t, J=7.7, 2H), 1.98-1.94 (br m, 2H), 1.84-1.69 (m, 7H), 1.54-1.48
(m, 1H).
##STR00067##
Example 50
5-(4-Methoxy-phenyl)-7-methyl-2-(3-piperidin-1-yl-propoxy)-5,6,7,8-tetrahy-
dro-[1,7]naphthyridine
##STR00068##
Step A. 2-Methoxy-6-methyl-pyridine. To a mixture of
6-methyl-pyridin-2-ol (10.0 g, 91.6 mmol) and Ag.sub.2CO.sub.3
(34.5 g, 125.1 mmol) in CHCl.sub.3 (300 mL) was added Mel (64.4 mL,
1.04 mol) over 30 min. The mixture was stirred for 48 h at rt in
the dark, then was filtered through a pad of SiO.sub.2, washing
with Et.sub.2O. The filtrate was concentrated to provide the title
compound (9.03 g, 80%). MS (ESI): mass calcd. for C.sub.7H.sub.9NO,
123.07; m/z found, 124.3 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3):
7.46-7.41 (m, 1H), 6.70 (d, J=7.2, 1H), 6.53 (d, J=8.2, 1H), 3.91
(s, 3H), 2.44 (s, 3H).
##STR00069##
Step B. 3-Bromo-6-methoxy-2-methyl-pyridine. A mixture of
2-methoxy-6-methyl-pyridine (15.2 g, 123 mmol) and
1,3-dibromo-5,5-dimethyl hydantoin (35.3 g, 123 mmol) in THF (1 L)
was stirred at rt for 48 h in the dark. The mixture was treated
with 10% aq. Na.sub.2S.sub.2O.sub.3 (100 mL) and stirred for 1 h.
The mixture was extracted with Et.sub.2O. The organic layer was
washed with H.sub.2O (2.times.), dried (MgSO.sub.4), and
concentrated. The residue was purified (SiO.sub.2; 0-5%
EtOAc/hexanes) to give the title compound (18.7 g, 76%). MS (ESI):
mass calcd. for C.sub.7H.sub.8BrNO, 200.98; m/z found, 202.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.60 (d, J=8.6, 1H), 8.45
(d, J=8.7, 1H), 3.90 (s, 3H), 2.54 (s, 3H).
##STR00070##
Step C. 3-Bromo-6-methoxy-2-methyl-pyridine N-oxide. A 5.degree. C.
solution of 3-bromo-6-methoxy-2-methyl-pyridine (20.8 g, 103 mmol)
in CHCl.sub.3 (550 mL) was treated with mCPBA (60%; 44.4 g, 154
mmol) slowly in portions over 1 h. The mixture was allowed to warm
to rt, and then was heated at 50.degree. C. for 18 h. The mixture
was cooled to rt, treated with 5% aq. Na.sub.2CO.sub.3 (300 mL),
and stirred for 1 h. The mixture was diluted with DCM and washed
with H.sub.2O (3.times.). The organic layer was separated, dried
(MgSO.sub.4), and concentrated to a light yellow oil (26.9 g). The
oil was purified (SiO.sub.2; 0-5% 2 M NH.sub.3 in MeOH/DCM) to give
the title compound (15.7 g, 70%). MS (ESI): mass calcd. for
C.sub.7H.sub.8BrNO.sub.2, 216.97; m/z found, 218.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.44 (d, J=8.9, 1H), 6.68 (d, J=9.0, 1H),
4.05 (s, 3H), 2.74 (s, 3H).
##STR00071##
Step D. Acetic acid 3-bromo-6-methoxy-pyridin-2-ylmethyl ester. A
solution of 3-bromo-6-methoxy-2-methyl-pyridine N-oxide (6.73 g,
30.9 mmol) in Ac.sub.2O (42 mL) was heated at 120.degree. C. for
3.5 h, then was cooled to rt. The mixture was diluted with MeOH
(250 mL) and concentrated (3.times.) to yield a brown oil (7.29 g),
which was purified (SiO.sub.2; 0-12% 2 M NH.sub.3 in MeOH/DCM) to
give the title compound (6.42 g, 80%). .sup.1H NMR (CDCl.sub.3):
7.65 (d, J=8.7, 1H), 6.58 (d, J=8.7, 1H), 5.22 (s, 2H), 3.89 (s,
3H), 2.17 (s, 3H).
##STR00072##
Step E. (3-Bromo-6-methoxy-pyridin-2-yl)-methanol. A mixture of
acetic acid 3-bromo-6-methoxy-pyridine-2-ylmethyl ester (3.94 g,
15.2 mmol) and 1 M aq. K.sub.2CO.sub.3 (26.2 mL, 26.2 mmol) in MeOH
(30 mL) was stirred at rt for 18 h. The mixture was concentrated,
diluted with H.sub.2O (15 mL), and extracted with DCM (3.times.).
The combined extracts were washed with H.sub.2O, dried, and
concentrated to give the title compound (2.97 g, 90%). MS (ESI):
mass calcd. for C.sub.7H.sub.8BrNO.sub.2, 216.97; m/z found, 218.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.68 (d, J=8.6, 1H), 6.60
(d, J=8.6, 1H), 4.67 (dd, J=4.7, 0.6, 2H), 4.01 (t, 4.7, 1H), 3.97
(s, 3H).
##STR00073##
Step F. 3-Bromo-6-methoxy-pyridine-2-carbaldehyde. A mixture of
(3-bromo-6-methoxy-pyridin-2-yl)-methanol (3.25 g, 14.9 mmol) and
MnO.sub.2 (9.07 g, 104 mmol) in CHCl.sub.3 (50 mL) was heated at
reflux for 18 h. The mixture was filtered while hot and the
filtrate was concentrated. The residue was purified (SiO.sub.2; 10%
EtOAc/hexanes) to yield the title compound (2.55 g, 80%). MS (ESI):
mass calcd. for C.sub.7H.sub.6BrNO.sub.2, 214.96; m/z found, 218.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 10.13 (s, 1H), 7.80 (d,
J=8.7, 1H), 6.83 (d, J=8.7, 1H), 3.99 (s, 3H).
##STR00074##
Step G. 3-Bromo-2-dimethoxymethyl-6-methoxy-pyridine. A solution of
3-bromo-6-methoxy-pyridine-2-carbaldehyde (4.63 g, 21.4 mmol) and
trimethylorthoformate (120 mL) in MeOH (200 mL) was treated with
conc. H.sub.2SO.sub.4 (4 mL). The mixture was stirred for 18 h,
then was treated with 5% aq. NaHCO.sub.3 (150 mL), with stirring,
and was extracted with DCM (5.times.). The combined organic
extracts were washed with brine (100 mL), H.sub.2O (100 mL), dried
(MgSO.sub.4), and concentrated to yield the title compound (5.07 g,
90%). .sup.1H NMR (CDCl.sub.3): 7.67 (d, J=8.6, 1H), 6.61 (d,
J=8.6, 1H), 5.56 (s, 1H), 3.95 (s, 3H), 3.52 (s, 6H).
##STR00075##
Step H.
2-Dimethoxymethyl-6-methoxy-3-[1-(4-methoxy-phenyl)-2-nitro-ethyl-
]-pyridine. A -78.degree. C. solution of
3-bromo-2-dimethoxymethyl-6-methoxy-pyridine (4.05 g, 15.4 mmol) in
toluene (120 mL) was treated with n-BuLi (1.6 M in hexanes; 10.6
mL, 17.0 mmol) over 15 min. After 40 min, a -78.degree. C. solution
of 1-methoxy-4-(2-nitro-vinyl)-benzene (2.99 g, 16.7 mmol) in
toluene (72 mL) was added over 8 min. After 1 h, a solution of
acetic acid (4 mL) in toluene (20 mL) was added dropwise at
-78.degree. C. After 30 min, the mixture was allowed to warm to rt,
was diluted with brine, and extracted with DCM (3.times.). The
combined organic extracts were dried and concentrated to yield
crude red oily product (7.30 g). Purification (SiO.sub.2; 0-15%
EtOAc/hexanes) gave the title compound (2.70 g, 48%). MS (ESI):
mass calcd. for C.sub.18H.sub.22N.sub.2O.sub.6, 362.15; m/z found,
363.4 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.39 (d, J=8.7, 1H),
7.21 (d, J=8.7, 2H), 6.85 (d, J=8.7, 2H), 6.63 (d, J=8.6, 1H), 5.76
(dd, J=6.7, 2.7, 1H), 5.28 (s, 1H), 4.93-4.85 (m, 2H), 3.92 (s,
3H), 3.77 (s, 3H), 3.53 (s, 3H), 3.49 (s, 3H).
##STR00076##
Step I.
2-Methoxy-5-(4-methoxy-phenyl)-5,6-dihydro-[1,7]naphthyridine. A
solution of
2-dimethoxy-methyl-6-methoxy-3-[1-(4-methoxy-phenyl)-2-nitro-ethyl]-pyrid-
ine (3.78 g, 10.4 mmol) in acetic acid (10 mL) was treated with Zn
powder (6.83 g, 104 mmol) and the mixture was heated at 40.degree.
C. for 18 h. The mixture was filtered, washing with MeOH. The
filtrate was concentrated to give a white solid, which was
dissolved in 6 N HCl (180 mL) and stirred for 18 h. The mixture was
cooled to 20.degree. C., neutralized with satd. aq. NaHCO.sub.3 to
pH.about.8, and extracted with DCM (3.times.). The combined organic
extracts were washed with H.sub.2O, dried (MgSO.sub.4), and
concentrated. Purification (SiO.sub.2; 5% 2 M NH.sub.3 in MeOH/DCM)
gave the title compound (3.18 g, 95%). MS (ESI): mass calcd. for
C.sub.16H.sub.16N.sub.2O.sub.2, 268.12; m/z found, 269.4
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.26 (s, 1H), 7.10 (d,
J=8.4, 1H), 7.00 (d, J=8.7, 2H), 6.84 (d, J=8.7, 2H), 6.50 (d,
J=8.4, 1H), 4.10 (m, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.33-3.36 (m,
1H), 3.04-2.99 (m, 1H).
##STR00077##
Step J.
2-Methoxy-5-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[1,7]naphthyrid-
ine. A solution of
2-methoxy-5-(4-methoxy-phenyl)-5,6-dihydro-[1,7]naphthyridine (3.18
g, 10.4 mmol) in EtOH (80 mL) was treated with NaBH.sub.4 (2.00 g,
52.9 mmol) in portions over 2 h. The mixture was stirred 18 h, then
was diluted with satd. aq. NaHCO.sub.3 (50 mL) and extracted with
DCM (3.times.). The combined organic extracts were washed with
H.sub.2O, dried (MgSO.sub.4), and concentrated. The residue was
purified (SiO.sub.2; 2-4% 2 M NH.sub.3 in MeOH/DCM) to give the
title compound (2.54 g, 90%). MS (ESI): mass calcd. for
C.sub.16H.sub.18N.sub.2O.sub.2, 270.14; m/z found, 271.4
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.26 (s, 1H), 7.10 (d,
J=8.4, 1H), 7.00 (d, J=8.7, 2H), 6.84 (d, J=8.7, 2H), 6.50 (d,
J=8.4, 1H), 4.12-3.96 (m, 3H), 3.91 (s, 3H), 3.79 (s, 3H),
3.39-3.31 (m, 1H), 3.04-2.99 (m, 1H).
##STR00078##
Step K.
2-Methoxy-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]n-
aphthyridine. A mixture of
2-methoxy-5-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[1,7]naphthyridine
(2.54 g, 9.40 mmol) and paraformaldehyde (4.22 g, 141 mmol) in MeOH
(50 mL) was heated at 55.degree. C. for 2.5 h, then was cooled to
rt and treated with NaBH.sub.4 (5.20 g, 136 mmol) in portions.
After 18 h at rt, the mixture was diluted with satd. aq.
NaHCO.sub.3 (until pH.about.8) and extracted with DCM. The combined
organic layers were washed with H.sub.2O, dried, and concentrated
to give the title compound (1.75 g, 65%). MS (ESI): mass calcd. for
C.sub.17H.sub.20N.sub.2O.sub.2, 284.15; m/z found, 285.4
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.10-7.05 (m, 3H), 6.85-6.80
(m, 2H), 6.47 (d, J=8.5, 1H), 4.16-4.10 (m, 1H), 3.90 (s, 3H), 3.78
(s, 3H), 3.75-3.77 (m, 1H), 3.59-3.52 (m, 1H), 3.03-2.97 (m, 1H),
2.53-2.47 (m, 1H), 2.44 (s, 3H).
##STR00079##
Step L.
5-(4-Methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridi-
n-2-ol. A solution of
2-methoxy-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyri-
dine (1.75 g, 6.15 mmol) in 4 M HCl (100 mL) was heated at reflux
for 5 h. The solution was concentrated to give
5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-2-ol
hydrochloride. The salt was neutralized with satd. aq. NaHCO.sub.3,
and extracted with DCM. The organic layer was concentrated to give
the title compound (1.14 g, 68%) as the free base. MS (ESI): mass
calcd. for C.sub.16H.sub.18N.sub.2O.sub.2, 270.33; m/z found, 271.4
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.12-7.07 (m, 2H), 7.03 (d,
J=9.3, 1H), 6.87-6.82 (m, 2H), 6.37 (d, J=9.3, 1H), 4.00-4.92 (m,
1H), 3.80 (s, 3H), 3.69-3.62 (m, 1H), 3.56-3.50 (m, 1H), 3.01-2.95
(m, 1H), 2.52-2.45 (m, 1H), 2.44 (s, 3H).
Step M. To a mixture of
5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-2-ol
(0.10 g, 0.37 mmol) and PPh.sub.3 (0.097 g, 0.37 mmol) in THF (5
mL) was added a solution of di-tert-butyldiazodicarboxylate (0.085
g, 0.37 mmol) in THF (5 mL). After 30 min, a solution of
3-piperidin-1-yl-propan-1-ol (0.053 g, 0.37 mmol) in THF (5 mL) was
added slowly. After 18 h, the mixture was concentrated, and the
resulting solid was purified (SiO.sub.2; 0-8% 2 M NH.sub.3 in
MeOH/DCM) to give the title compound (30 mg, 20%). MS (ESI): mass
calcd. for C.sub.24H.sub.33N.sub.3O.sub.2, 395.26; m/z found, 396.6
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.10-7.04 (m, 3H), 6.83 (d,
J=8.6, 2H), 6.45 (d, J=8.4, 1H), 4.33-4.25 (m, 2H), 4.15-4.10 (m,
1H), 3.79 (s, 3H), 3.76-3.70 (m, 1H), 3.57-3.50 (m, 1H), 3.02-2.97
(m, 1H), 2.53-2.45 (m, 3H), 2.44 (s, 3H), 2.42-2.38 (m, 3H),
2.00-1.92 (m, 2H), 1.66-1.54 (m, 7H).
##STR00080##
Example 51
5-(4-Methoxy-phenyl)-7-methyl-2-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tetr-
ahydro-[1,7]naphthyridine
##STR00081##
Step A.
2-Chloro-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]na-
phthyridine. A solution of
5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-2-ol
hydrochloride (153 mg, 0.499 mmol) in POCl.sub.3 (1 mL) was heated
at 100.degree. C. for 6 h. The mixture was cooled to rt, and was
poured into a stirring mixture of ice and satd. aq. NaHCO.sub.3,
and was extracted with DCM (4.times.). The combined organic layers
were washed with H.sub.2O and brine, dried (MgSO.sub.4), and
concentrated to give the title compound (180 mg), which was carried
directly on to the next step. MS (ESI): mass calcd. for
C.sub.16H.sub.17ClN.sub.2O, 288.10; m/z found, 289.8
[M+H].sup.+.
Step B. A flask containing a mixture of
2-chloro-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyrid-
ine (0.080 g, 0.28 mmol), Et.sub.2NH (1.0 mL),
1-but-3-ynyl-piperidine (0.077 g, 0.56 mmol), CuI (5.3 mg, 27.8
umol), PPh.sub.3 (36 mg, 0.14 mmol), and
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.020 g, 0.028 mmol) in DMF (0.5 mL)
was evacuated and back-filled with N.sub.2 (3.times.). The mixture
was heated at 105 C for 18 h, then was cooled to rt, diluted with
satd. aq. NaHCO.sub.3, and extracted with DCM. The combined organic
layers were washed with H.sub.2O, dried, and concentrated. The
residue was purified (SiO.sub.2; 0-6% 2 M NH.sub.3 in MeOH/DCM) to
give the title compound (35 mg, 33%). MS (ESI): mass calcd. for
C.sub.25H.sub.31N.sub.3O, 389.25; m/z found, 390.6 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.15-7.08 (m, 2H), 7.06 (d, J=8.7, 2H),
6.83 (d, J=8.7, 2H), 4.23-4.17 (m, 1H), 3.91-3.85 (m, 1H), 3.79 (s,
3H), 3.66-3.59 (m, 1H), 3.05-2.99 (m, 1H), 2.76-2.62 (m, 4H),
2.56-2.46 (m, 5H), 2.45 (s, 3H), 1.68-1.58 (m, 4H), 1.49-1.40 (m,
2H).
Biological Methods
H.sub.3 Receptor Binding
Binding of compounds to the cloned human H.sub.3 receptor, stably
expressed in SK-N-MC cells, was performed (Lovenberg, T. W. et al.
J. Pharmacol. Exp. Ther. 2000, 293, 771-778). Briefly, cell pellets
from SK-N-MC cells expressing the human H.sub.3 receptor were
homogenized in 50 mM Tris-HCl/5 mM EDTA and re-centrifuged at
30,000 g for 30 min. Pellets were re-homogenized in 50 mM Tris/5 mM
EDTA (pH 7.4). Membranes were incubated with 0.8 nM
N-[.sup.3H]-.alpha.-methylhistamine plus/minus test compounds for
60 min at 25.degree. C. and harvested by rapid filtration over GF/C
glass fiber filters (pretreated with 0.3% polyethylenimine)
followed by four washes with ice-cold buffer. Nonspecific binding
was defined in the presence of 10 .mu.M histamine. IC.sub.50 values
were determined by a single site curve-fitting program (GraphPad,
San Diego, Calif.) and converted to K.sub.i values based on a
N-[.sup.3H]-.alpha.-methylhistamine K.sub.d of 800 pM and a ligand
concentration of 800 pM (Cheng & Prusoff, Biochem. Pharmacol.
1973, 22, 3099-3108). Data are presented in Table 1.
Rat Brain SERT
A rat brain without cerebellum (Zivic Laboratories,
Inc.-Pittsburgh, Pa.) was homogenized in a 52.6 mM Tris pH 8/126.4
mM NaCl/5.26 mM KCl mixture and centrifuged at 1,000 rpm for 5 min.
The supernatant was removed and re-centrifuged at 15,000 rpm for 30
min. Pellets were re-homogenized in a 52.6 mM Tris pH8/126.4 mM
NaCl/5.26 mM KCl mixture. Membranes were incubated with 0.6 nM
[.sup.3H]-Citalopram plus/minus test compounds for 60 min at
25.degree. C. and harvested by rapid filtration over GF/C glass
fiber filters (pretreated with 0.3% polyethylenimine) followed by
four washes with ice-cold buffer. Nonspecific binding was defined
in the presence of 100 .mu.M fluoxetine. IC.sub.50 values were
determined by a single site curve-fitting program (GraphPad, San
Diego, Calif.) and converted to K.sub.i values based on a
[.sup.3H]-Citalopram K.sub.d of 0.6 nM and a ligand concentration
of 0.6 nM. Data are presented in Table 1.
TABLE-US-00005 TABLE 1 Rat SERT Human H.sub.3 EX K.sub.i (nM)
K.sub.i (nM) 1 1000 1 2 191 2 3 569 5 4 1667 1 5 1200 1 6 2284 4 7
583 4 8 34 12 9 43 3 10 20 4 11 53 43 12 29 90 13 179 1 14 59 8 15
20 5 16 15 18 17 312 2 18 186 9 19 56 208 20 129 23 21 15 7 22 87
3000 23 30 2 24 269 2 25 194 1 26 64 44 27 144 7 28 129 264 29 19
13 30 33 16 31 15 4 32 2000 2 33 142 1 34 186 2 35 26 7 36 22 15 37
18 13 38 56 50 39 233 42 40 45 13 41 23 13 42 106 3000 43 137 796
44 74 18 45 101 4 46 17 13 47 1000 11 48 1000 45 49 623 78 50 4 1
51 21 11
Human SERT
Homogenized HEK293 (Human Embryonic Kidney) membranes expressing
the human SERT were incubated with .sup.3H-citalopram (SERT) at rt
for 1 h in 50 mM Tris, 120 mM NaCl, 5 mM KCl (pH 7.4). Nonspecific
binding was determined in the presence of 10 .mu.M fluoxetine for
the SERT. The membranes were washed and the radioactivity was
counted as above. Calculations for K.sub.i at the SERT were based
on a K.sub.d value for .sup.3H-citalopram and a ligand
concentration of 3.1 nM. Data are presented in Table 2.
TABLE-US-00006 TABLE 2 Human SERT EX K.sub.i (nM) 1 3000 2 768 3
1137 4 2333 5 NT 6 147 7 2000 8 107 9 NT 10 NT 11 189 12 70 13 NT
14 303 15 33 16 120 17 1032 18 362 19 51 20 226 21 26 22 NT 23 141
24 NT 25 1333 26 611 27 826 28 NT 29 66 30 30 31 93 32 NT 33 NT 34
NT 35 147 36 106 37 37 38 NT 39 NT 40 62 41 31 42 NT 43 1021 44 70
45 NT 46 16 47 NT 48 2000 49 2000 50 7 51 32 NT = not tested
Cyclic AMP Accumulation
Sublines of SK-N-MC cells were created that expressed a reporter
construct and the human H.sub.3 receptor. The reporter gene
(.beta.-galactosidase) is under the control of multiple cyclic AMP
responsive elements. In 96-well plates, histamine was added
directly to the cell media followed 5 min later by an addition of
forskolin (5 .mu.M final concentration). When appropriate,
antagonists were added 10 min prior to agonist addition. After a
6-h incubation at 37.degree. C., the media was aspirated and the
cells washed with 200 .mu.L of phosphate-buffered saline followed
by a second aspiration. Cells were lysed with 25 .mu.L 0.1.times.
assay buffer (10 mM Na-phosphate, pH 8, 0.2 mM MgSO.sub.4, 0.01 mM
MnCl.sub.2) and incubated at rt for 10 min. Cells were then
incubated for 10 min with 100 .mu.L of 1.times. assay buffer
containing 0.5% Triton and 40 mM .beta.-mercaptoethanol. Color was
developed using 25 .mu.L of 1 mg/mL substrate solution
(chlorophenolred .beta.-D galactopyranoside; Roche Molecular
Biochemicals, Indianapolis, Ind.) Color was quantitated on a
microplate reader at absorbance 570 nM. The pA.sub.2 values were
calculated by Schild regression analysis of the pEC.sub.50 values
and are presented in Table 3.
TABLE-US-00007 TABLE 3 EX pA.sub.2 1 9.1 2 9.0 4 9.1 5 8.7 6 8.2 7
9.2 13 9.0 15 7.9 16 7.7 17 8.6 18 8.4 21 7.8 23 8.4 24 8.6 25 9.0
31 8.4 32 8.6 33 8.5 34 9.0 47 7.9
* * * * *